February 2014

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • February 2014 • Vol. 9, No. 2

INSIDE SOLID TUMORS New genomic tool gauges breast cancer risk ............ 24 Patient symptoms before aromatase inhibitor therapy predict adherence ............ 27 HEMATOLOGIC DISEASE Obinutuzumab superior to rituximab among CLL patients with comorbidities ........................ 7 CURRENT PRACTICE

IMAGES in ONCOLOGY

SABCS 2013

A Conclusion to the Bisphosphonate Controversy?

San Antonio—A large meta-analysis presented at the recent San Antonio Breast Cancer Symposium (SABCS) has tried to end the long-standing controversy over whether adjuvant bisphosphonates can act as an anticancer therapy in women with breast cancer. The study concluded that bisphosphonates are capable of reducing bone recurrence by 34% and breast cancer death by 17%, but only in postmenopausal women and those who have chemotherapy-induced menopause.

“The involvement of the 20,000 see BISPHOSPHONATES, S page 14

Maurie Markman, MD: The large, long, expensive ‘definitive’ clinical trial ............................. 6 Oncologists’ perspective: From private practice to hospital employee ........... 15 Morie Gertz, MD: How I manage hematopoietic stem cell transplantation in Waldenström’s macroglobulinemia .......... 22 Clinical Conundrums ....................... 26

Image courtesy of Science Photo Library

ASH 2013

Targeted Therapy Improves Survival in Hard-to-Treat CLL New Orleans—Relative to rituximab alone, a novel, first-in-class therapy called idelalisib significantly improved both progression-free (PFS) and overall survival (OS) in a study of patients with chronic lymphocytic leukemia (CLL) who had few other therapeutic options.

The interim efficacy and safety data presented as a late breaker at the 2013 annual meeting of the American Society of Hematology suggests a significant breakthrough in CLL. The patients were heavily pretreated and not considered eligible for standard cytotoxic chemotherapy.

Idelalisib “affords an opportunity not see IDELALISIB, B page 6

Leukemia blood cells.

Pay-for-Delay Deals Increase Cancer Drug Costs Cancer drugs a special target for shady deals between brand-name and generic drug makers

I

n 2003, Barbara Hart, JD, served as lead counsel on an antitrust lawsuit focused on tamoxifen (Nolvadex), the most widely prescribed cancer drug in the world.

“We were retained by both individual tamoxifen patients and benefit fund end payers who all felt strongly about this case,” said Ms. Hart, currently chief operating officer at Lowey Dannenberg Cohen & Hart, in White Plains, N.Y. The lawsuit addressed a controversial deal forged between two drug companies. In March 1993, brand-name drug manufacturer AstraZeneca agreed to pay $21 million directly to generic manufacturer Barr Laboratories, in exchange for Barr’s consent to not market a less expensive generic version of tamoxifen until AstraZeneca’s patent expired in August 2002. The agreement also stipulated that Barr could sell AstraZeneca-manufactured tamoxifen at a 15% discount before patent expiration.

The agreement between AstraZeneca and Barr, known as “reverse payment” or “payfor-delay,” sparked 30 lawsuits throughout the United States, culminating in a class action complaint. The complaint specified that the pay-for-delay agreement between see PAY-FOR-DELAY, Y page 12

RE VIE W S & COMMENTAR IES

Expert Insights From City of Hope In update, tasquinimod continues to prolong PFS in metastatic CRPC .............................. 10 C.A. Stein, MD, PhD

Sunitinib hepatocellular cancer trial ended for futility ........................ 11 Vincent Chung, MD

Established treatment, demonstrated results Single-agent TREANDA® (bendamustine HCl) for Injection provided durable responses that lasted a median of 9 months

Median DR

9.2 months (95% CI: 7.1, 10.8)

All responders (n=74) Patients who achieved a CR/CRu

10.4 months (95% CI: 9.3, 13.6)

1

8.3 months (95% CI: 6.3, 10.8)

Patients who achieved a PR

1

0

2

4

6

8

10

12

Months

The efficacy of TREANDA was evaluated in a single-arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine.

Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppressionrelated adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections.

Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined.

Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities (frequency ≥ 15%) are lymphopenia, leukopenia, anemia, neutropenia, and thrombocytopenia.

Please see accompanying brief summary of Full Prescribing Information on following pages.

Learn more at TREANDAHCP.com.

Reference: 1. Data on file. Teva Pharmaceuticals.

© 2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40313 December 2013.

Brief Summary of Prescribing Information for Indolent B-cell NonHodgkin’s Lymphoma That Has Progressed 1 INDICATIONS AND USAGE TREANDA® is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

2 DOSAGE AND ADMINISTRATION 2.2 Dosing Instructions for NHL Recommended Dosage: g The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.

Dose Delays, y , Dose Modifications and Reinitiation of Therapy py for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant * Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ) Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) * 1 x 109/L, platelets * 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.

2.3 Reconstitution/Preparation for Intravenous Administration Ãi«Ì V> ÞÊÀiV ÃÌ ÌÕÌiÊi>V Ê/, ÊÛ > Ê>ÃÊv ÜÃ\ÊUÊÓxÊ }Ê/, Ê vial: Add 5 mL of only Sterile Water for Injection, USP°Ê UÊ £ääÊ }Ê TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

2.4 Admixture Stability TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.

3 DOSAGE FORMS AND STRENGTHS TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 2). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy.

Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be * 1 x 109/L and the platelet count should be * 75 x 109/L. [See Dosage and Administration (2.2)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reac-

tions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy.

However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.

5.7 Extravasation Injury TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain.

Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions]] of the label: Myelosuppression (5.1); Infections (5.2); Infusion Reactions and Anaphylaxis (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasion Injury (5.7). The data described below reflect exposure to TREANDA in 176 patients who participated in two single-arm trials for the treatment of indolent B-cell NHL. 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.

6.2 Clinical Trials Experience in NHL The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 1. The most common non-hematologic adverse reactions (* 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (* 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 1: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA by System Organ Class and Preferred Term (N=176) Number (%) of patients* System organ class Preferred term All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain Infections and infestations Herpes zoster Upper respiratory tract infection Urinary tract infection

176 (100)

94 (53)

13 (7)

0

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

18 (10) 18 (10) 17 (10)

5 (3) 0 4 (2)

Number (%) of patients* All Grades Grade 3/4 0 15 (9) 9 (5) 14 (8) 11 (6) 11 (6) 2 (1) 11 (6) 0 11 (6)

System organ class Preferred term Sinusitis Pneumonia Febrile neutropenia Oral candidiasis Nasopharyngitis Investigations Weight decreased Metabolism and nutrition disorders Anorexia Dehydration Decreased appetite Hypokalemia Musculoskeletal and connective tissue disorders Back pain Arthralgia Pain in extremity Bone pain Nervous system disorders Headache Dizziness Dysgeusia Psychiatric disorders Insomnia Anxiety Depression Respiratory, thoracic and mediastinal disorders Cough Dyspnea Pharyngolaryngeal pain Wheezing Nasal congestion Skin and subcutaneous tissue disorders Rash Pruritus Dry skin Night sweats Hyperhidrosis Vascular disorders Hypotension

31 (18)

3 (2)

40 (23) 24 (14) 22 (13) 15 (9)

3 (2) 8 (5) 1 (<1) 9 (5)

25 (14) 11 (6) 8 (5) 8 (5)

5 (3) 0 2 (1) 0

36 (21) 25 (14) 13 (7)

0 0 0

23 (13) 14 (8) 10 (6)

0 1 (<1) 0

38 (22) 28 (16) 14 (8) 8 (5) 8 (5)

1 (<1) 3 (2) 1 (<1) 0 0

28 (16) 11 (6) 9 (5) 9 (5) 8 (5)

1 (<1) 0 0 0 0

10 (6)

2 (1)

*Patients may have reported more than 1 adverse reaction.

NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 2. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Hematology variable

Percent of patients All Grades

Grades 3/4

Lymphocytes Decreased

99

94

Leukocytes Decreased

94

56

Hemoglobin Decreased

88

11

Neutrophils Decreased

86

60

Platelets Decreased

86

25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in * 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient).

Cardiac enzymes and ejection fractions remained normal in all patients.

No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

4

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16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. TREANDA is an antineoplastic product. Follow special handling and disposal procedures1.

16.2 How Supplied TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial.

16.3 Storage TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd or its affiliates. All rights reserved.

8/2013 (Label Code: 00016287.06) TRE-40157 This brief summary is based on TRE-008 TREANDA full Prescribing Information.

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD University of California, San Diego, CA

Michael A. Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Oncology Nursing

Hematologic Malignancies Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Mayo Clinic Rochester, MN

Syed A. Abutalib, MD

Leonard Saltz, MD

Cancer Treatment Centers of America Zion, Illinois

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

Mission Statement Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MD

T

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Medical Oncologist New York, NY

Editorial Philosophy Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Steven D. Passik, PhD

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Albert Einstein College of Medicine, New York, NY

Infection Control

Mercy Medical Center St. Louis, MO

Edward S. Kim, MD

Richard J. Gralla, MD

VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

John W. Finnie, MD

Lung g and Head and Neck Cancers

Lung g Cancer,, Emesis

Matt Brow

Community Oncology

Genitourinary y Cancer Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

The Pritchard Group Rockville, MD

University of Colorado Cancer Center Denver, CO

The Mount Sinai Medical Center New York, NY

Ephraim Casper, MD

Ronald M. Bukowski, MD

Mary Lou Bowers, MBA

Cindy O’Bryant, PharmD

Sara S. Kim, PharmD

Richard Stone, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Policy and Management

Pharmacy

Cathy Eng, MD

Gastrointestinal Cancer and Sarcoma

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

University of Alabama Birmingham, AL

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD

Gastrointestinal Cancer

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Harry Erba, MD, PhD Maura N. Dickler, MD

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Jennifer R. Brown, MD, PhD Andrew Seidman, MD

Bioethics

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content.

Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

The Large, Long, Expensive ‘Definitive’ Clinical Trial Can’t we do better?

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

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recently reported Phase III trial that examined the utility of intermittent versus continuous androgen deprivation therapy for metastatic prostate cancer provides the background for this commentary. Before proceeding, I’d like to make clear that the intent of this alltoo-brief discussion is nott to criticize the thoughtful and clinically relevant efforts of the study’s investigators. I am also not suggesting that anything specific should have been done to improve the study’s likelihood of a different outcome.

Rather, my goal is to examine a few specific issues that may not be considered particularly important to study investigators or the academic community when a trial is initiated, but just possibly may be of far greater significance to current and future patients (and their families), as well as a large segment of the practicing community of oncologists.

A brief description of the study is required. The trial was designed to address the question of whether

intermittent androgen deprivation therapy for newly diagnosed metastatic prostate cancer would produce a therapeutic equivalent (“noninferior”) survival outcome.1 It also evaluated the impact of the two treatment strategies on quality of life as a co-primary objective.

A total of 3,040 patients were enrolled over a period of 13 years (1995-2008).

With a median follow-up of almost 10 years, the median overall survival for continuous versus intermittent therapy was 5.8 versus 5.1 years, respectively (hazard ratio, 1.10; 90% confidence interval, 0.99-1.23). The authors concluded that “our findings are statistically inconclusive,” adding that “too few events occurred to rule out significant inferiority of intermittent therapy.”

So, this study involving several thousand patients (issue 1), which took 18 years from initial patient entry until publication in the peer-reviewed literature (issue 2), and was funded in part by the National Cancer Institute and cost U.S. taxpayers an unspecified but clearly large sum (issue 3), was unable to provide an answer to the proposed question (issue 4). Or perhaps more correctly stated, the answer could not be provided based on the study’s design (issue 5).

It should be asked: Was it really necessary to define “noninferiority” (leading to the study’s conclusion) in such a strict manner that this large sample size, accrued over an extended period, was required? If the answer to this question

is yes, what specific “authority” made this determination and what was their specific clinically relevant justification?

And if the answer is no, perhaps the next time a similar study is contemplated, an alternative design should be employed that can provide a more “definitive” answer in a far shorter period of time and require a much smaller sample size. (It is notable that other investigators have studied the question posed in this trial using a randomized setting and apparently believed it to be appropriate to employ far smaller sample sizes.2) It might be argued that the specific intent of this trial was to somehow provide a truly “definitive answer” to the question, and therefore the very large patient population was required. But again, we should ask: What authority has defined the requirements of a “definitive answer”? What is wrong with conducting a well-designed Phase III study, presenting the objectively evaluated survival and toxicity outcomes, and then permitting patients, after they have had discussions with their advisors (family, etc.) and physicians, to decide for themselves how a specific trial’s results will impact their treatment choices?

Again, I am not trying to criticize this individual study, but rather to raise a series of disquieting questions that, in my opinion, deserve additional discussion and even rigorous debate over how to optimize our search for meaningful

answers to important clinical questions, both within the oncology investigative community and among other interested parties (e.g., pharmaceutical companies; drug regulatory and research funding agencies; third-party health care payers; patient advocacy groups; and the general public, who comprise the future cancer patient population and are responsible for paying the bill for government-sponsored clinical trials).

A study of this size, taking this long, costing what this trial must have cost, and producing “findings [that] are statistically inconclusive” will, hopefully, lead many to ask one additional question: Can’t we do better?

within 24 months of their last therapy and measurable lymphadenopathy.

The 220 participants in the trial were randomized to receive idelalisib in combination with rituximab or rituximab and placebo. The 150 mg dose of idelalisib, like the placebo, was taken twice daily

and continued until disease progression.

The six-month rituximab treatment protocol was the same in both arms. After an initial 375 mg/m2 dose, 500 mg/m2 of rituximab was administered every two weeks for four cycles and then every four weeks for three cycles.

On the primary end point of PFS, the hazard ratio (HR) was 0.15 (P ( <0.0001) for the idelalisib arm relative to rituximab alone. The median PFS has not yet been reached in the idelalisib arm but was 5.5 months for rituximab alone. Although the median OS has not yet been reached in either group, the HR for this outcome is already significant—0.28 in the idelalisib arm relative to rituximab alone (P ( =0.018). The advantage for the idelalisib arm in terms of objective response rate also was significantly greater (P ( <0.0001). Dr. Furman emphasized that these advantages were remarkably consistent across subgroups, including those stratified by presence or absence of prognostically significant mutations, such as del(17p)/ TP53 mutation.

Given the poor fitness of the study population, which had an average CIRS of 8, the tolerability of the regimen is notable. Although 2.7% of patients in the idelalisib arm had a drug dose reduction because of an adverse event,

References 1. Hussain M, Tangen CM, Berry DL, et al.

Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med. 2013;368:1314-1325, PMID: 23550669.

2. Niraula S, Le LW, Tannock IF. Treatment of prostate cancer with intermittent versus continuous androgen deprivation: A systematic review of randomized trials. J Clin Oncol. 2013;31:2029-2036, PMID: 23630216.

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

HEMATOLOGIC DISEASE

IDELALISIB continued from page 1

just to treat refractory disease effectively but to do so much more safely than we ever have done before,” Richard Furman, MD, who heads the CLL program at Weill Cornell Medical College in New York City, said. According to Dr. Furman, who presented the trial results, idelalisib is a highly targeted oral therapy that inhibits the delta isoform of phosphoinositide 3-kinase (PI13K-δ), which is important in a variety of cell functions.

One of the key inclusion criteria for the double-blind trial, which included centers in several countries, was that patients had to be unfit for cytotoxic therapies. This was defined as a sufficient burden of comorbidities to produce a Cumulative Illness Rating Score (CIRS) of at least 6, advanced renal impairment or significant cytopenias. The heavily pretreated patients also were required to have had progression

Idelalisib performed better than rituximab in a number of clinically relevant measures, strongly supporting use of the drug as second-line therapy for CLL.

Chronic lymphocytic leukemia cells.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

Obinutuzumab Superior to Rituximab in CLL Improved outcomes seen for patients with comorbidities New Orleans—In previously untreated patients with chronic lymphocytic leukemia and comorbidities, the novel CD20-targeted monoclonal antibody obinutuzumab is more active than rituximab, according to results of a Phase III trial that paired both with chlorambucil.

This finding included a significant advantage in progression-free survival (PFS), the study’s primary end point, leading the investigators to conclude that obinutuzumab (GA101, Roche) is the better choice in this setting.

“GA101 in combination with chlorambucil is superior to rituximab with chlorambucil in regard to PFS, to complete remissions and to molecular responses. This means a potentially practicechanging treatment advance for this large patient population,” said Valentin Goede, MD, a hematologist/oncologist at University Hospital in Cologne, Germany, and a member of the German CLL Study Group. Presenting the data at the 2013 annual meeting of the American Society of Hematology (ASH), Dr. Goede noted a trend for an overall survival (OS) advantage after a median follow-up of just 19 months.

For entry into the trial, which included two stages of analysis, patients with chronic lymphocytic leukemia (CLL) were required to be treatment-naive and have a Cumulative Illness Rating Scale (CIRS) score of 6 or greater or a creatinine clearance of less than 70 mL/min.

These criteria were intended to identify patients who would be considered ineligible for more aggressive regimens, such as those anchored with fludarabine.

In the first analysis, which was reported previously, both of the arms containing a monoclonal antibody were superior to chlorambucil alone, turning the focus in this second stage of analysis to the comparison between the remaining two arms. Obinutuzumab was administered at a dose of 100 mg on day 1, 900 mg on day 2, and 1,000 mg on days 8 and 15 during the first of six 28-day cycles.

In the five subsequent cycles, obinutuzumab was administered at a dose of 1,000 mg on day 1. Rituximab was administered at a dose of 375 mg/m2 on day 1 of the first cycle and 500 mg/ m2 on day 1 of all the subsequent five cycles. Oral chlorambucil was administered at a dose of 0.5 mg/kg on day 1 and day 15 of all cycles in both arms.

The median PFS was 26.7 months for 333 patients randomized to the obinutuzumab regimen and 15.2 months for 330 patients given the rituximab regimen. This translated into a hazard ratio (HR) of 0.39, significantly in favor of obinutuzumab (95% confidence interval, 0.31-0.49; P<0.0001). Observed differences in complete response (21% vs.

7%) and proportion of negative minimal residual disease (MRD) blood samples at the end of treatment (29.4% vs. 2.5%) also greatly favored obinutuzumab.

The proportion of patients experiencing a grade 3 or higher adverse event was higher on obinutuzumab (66% vs.

47%), but Dr. Goede reported that this difference was primarily due to a higher rate of infusion reactions (20% vs.

4%). In contrast, the rates of grade 3 or higher neutropenia were slightly greater (33% vs. 27%) and the rates of grade 3 or greater infection during treatment were the same (7% in each group).

Although OS data remains preliminary, at the time of reporting the HR of 0.66 ((P<0.08) favored obinutuzumab.

Overall, the data suggests that the engineered obinutuzumab antibody is

superior to rituximab for CLL at least in this setting, particularly in the context of an acceptable safety profile.

Dr. Goede indicated that obinutuzumab plus chlorambucil appears likely to be recognized as highly active in this patient population, but it also may increase the likelihood of sustained remissions when combined with one of several other promising agents emerging for the treatment of this disease.

“For the future, one can ask in regard to our concept for treating these patients whether we may expand from symptom control to long-lasting disease control,” Dr. Goede said.

Alex Danilov, MD, PhD, a hematologist/oncologist at Dartmouth-Hitchcock Norris Cotton Cancer Center in Lebanon, N.H, called the substantial rate of MRD “impressive.” He characterized the results overall as “very encouraging” because effective regimens in CLL patients with comorbidities has been “an unmet need.”

However, Dr. Danilov suggested that the data from this study introduces a number of questions that need to be pursued. He outlined three: 1. Will obinutuzumab still be associated with a PFS advantage in patients who are able to tolerate the more effective regimens used in elderly but relatively fit patients, such as those containing bendamustine?

2. Will obinutuzumab also confer benefit when used in combination with novel agents, such as ibrutinib (Imbruvica, Johnson & Johnson/Pharmacyclics) and other inhibitors of BCR-associated kinases?

3. How much of a problem will obinutuzumab-associated infusion reactions be for elderly patients, who often have a poor tolerance for the IV steroids used to manage these reactions?

Based on the data reported at ASH, Dr. Danilov believes that “obinutuzumab

compared with none of those taking rituximab alone, only 8.2% of those on idelalisib versus 11.2% of those on rituximab alone, had an adverse event leading to drug discontinuation. More patients receiving idelalisib reported chills (22% vs. 16%) and pyrexia (29% vs. 16%), but many side effects were numerically more common in the group receiving rituximab alone, including infusion-related reactions.

The high rate of tolerability is attributed to the specificity of idelalisib’s action. Idelalisib inhibits the P13K-δ isoform of the P13 pathway and has been shown not only to inhibit

proliferation and induce apoptosis of CLL cells in experimental settings, but also to inhibit the retention of CLL cells in lymphoid tissues, Dr. Furman said.

This latter effect may explain the relatively large reduction in lymphadenopathy in patients taking idelalisib. The lymph node response rate, defined as at least a 50% reduction in lymph node size, was 93% in those receiving idelalisib versus 4% on rituximab alone (HR, 264.5; P<0.0001).

According to Dr. Furman, the study results “herald a dawn in a new age for CLL,” and the results appear to support this claim. The activity of the

therapy is enhanced by what appears to be an uncommon specificity in the drug’s effect on target malignant cells.

Brian Hill, MD, PhD, a hematologist/ oncologist at the Taussig Cancer Institute at Cleveland Clinic in Ohio, who was not involved in the study, said the data should be considered of “immediate interest to clinicians.” Noting that there was a 93% nodal response rate in a group with pretreated CLL, he observed that idelalisib was generally well tolerated and “unequivocally superior” to rituximab monotherapy.

“Due to resounding evidence of meaningful clinical benefit, an independent

The study raises as many questions as it answers.

Obinutuzumab (GA101) targets CD20 and kills B cells.

has a strong potential to change oncology practice in the future,” not only in elderly patients with comorbidities but other populations, pending results from ongoing studies. For example, Dr. Danilov said, “It would be of great interest to study obinutuzumab in fludarabine combinations with the potential of also incorporating this agent in therapy of younger patients with CLL.” —Ted Bosworth Dr. Goede has had relevant financial relationships with Mundipharma and Hoffman-La Roche. Dr. Danilov has no relevant conflicts of interest.

data monitoring committee recommended premature discontinuation of the study,” Dr. Hill observed. The data “strongly support the use of this regimen as second-line therapy for CLL, particularly those who are not fit for treatment with conventional chemotherapeutic agents.”

—Ted Bosworth Dr. Furman has received research funding and has served on advisory committees for Gilead Sciences. Dr. Hill is on the advisory boards for Genentech and Seattle Genetics and serves on speaker bureaus for Celgene, Genentech, Janssen, Seattle Genetics and Teva.

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REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

Expert Insights From City of Hope Each month, Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from a top cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care.

This month we introduce City of Hope. We hope you find this Reviews & Commentaries section, both here and with additional commentaries on our website at clinicaloncology.com, to be a valuable tool.

City of Hope: Collaborative Research and Clinical Expertise

IImages and d text t t provided id d by b Cit City off Hope.

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Above, a panorama of the City of Hope campus in Duarte, Calif. At left, a view of the buildings housing the Beckman Research Institute and the Gonda Center for Diabetes and Genetic Research.

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ity of Hope, a nationally known biomedical research, treatment and education institution near Los Angeles, is focused on rapidly transforming scientific discoveries into better cancer treatments and better prevention strategies.

Its mission is to shorten the time from initial research idea to approval of a new treatment in order to quickly bring cures to patients. Designated as a Comprehensive Cancer Center by the National Cancer Institute, City of Hope is also a founding member of the National Comprehensive Cancer Network.

In a multidisciplinary, interactive environment, more than 200 physicians and scientists involved in basic, clinical, translational and prevention research collaborate to develop innovative, cancer-fighting therapies. Their work is a continuum, starting with explorations of the biomedical mechanisms of oncogenesis and progression, moving on to the development of new treatments and the testing of those treatments in clinical trials, and, finally, delivering the best in patient care. This work furthers the understanding of cancer risk assessment and prevention.

Research conducted at City of Hope has led to recombinant DNA technology and the identification of monoclonal antibodies, which in turn led to the development of synthetic human insulin and four of the top-selling cancer drugs, including bevacizumab and rituximab (Avastin

and Rituxan, both from Genentech). City of Hope is also a pioneer in the fields of bone marrow transplantation and cancer genetics.

At any given time, City of Hope has more than 30 investigational new drug applications, an exceptionally large number for an organization of City of Hope’s size, reflecting its commitment to innovation and speeding treatments to patients.

City of Hope also holds more than 200 patents.

The Comprehensive Cancer Center encompasses both the Beckman Research Institute and the City of Hope Medical Center, and also includes the Irell & Manella Graduate School of Biological Sciences. Major facilities include the City of Hope Helford Clinical Research Hospital and the Center for Biomedicine and Genetics, a manufacturing facility specializing in the production of pharmaceutical materials.

This manufacturing facility is one of three at City of Hope dedicated to the manufacture of potential new therapies, including biologics and small molecules, enabling investigators to create promising treatments without the high cost and delays encountered by other research centers. These capabilities save years of development time and ensure that City of Hope can rapidly and efficiently translate discoveries into beneficial care.

Some of the cancers researched and treated at City of Hope include hematologic

malignancies and solid tumors, including breast, genitourinary/prostate, thoracic/lung, gastrointestinal/liver, musculoskeletal, gynecologic, and brain cancers, as well as several pediatric cancers.

There are five major areas of research at the center: • The Molecular Oncology program conducts basic laboratory research, contributing to the understanding of the underlying genetic, molecular and biological bases of cancer.

• The Developmental Cancer Therapeutics program, the Cancer Immunotherapeutics program, and the Hematologic Malignancies program all translate laboratory observations into patient treatments as part of City of Hope’s emphasis on both clinical and translational research.

• The Cancer Control and Population Sciences program focuses on four areas of concentration: host and environmental determinants of cancer; health-related outcomes and quality of life after cancer; interventional studies to reduce cancer-related morbidity; and educational initiatives.

Founded in 1913, City of Hope collaborates with colleagues around the world, participating in more than 500 projects with more than 400 institutions in 40 states and more than 30 countries.

In the research of advanced cancers

What if inhibiting the PD-1 checkpoint pathway played an important role in restoring immune response to tumor cells?

In a normal state, the immune system recognizes tumors and can mount an active antitumor response1,2 Antigen-presenting cell

Step 1: Tumor releases antigen3

Active T cells

Step 2: Antigen-presenting cells activate T cells that proliferate and migrate to the tumor.

T cells then release apoptosisinducing proteins, which attack the tumor cells3,4

Tumor

One way that tumors can evade normal immune attack is through exploitation of the PD-1 checkpoint pathway via the PD-1 receptor, a key regulator of T-cell activity, by converting active T cells to inactive T cells5-8

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 ligands on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway.

This inhibits activated T cells and suppresses T-cell attack 6-9

PD-1 receptor

Inactive T cells

Bristol-Myers Squibb is researching ways to block the interaction between the PD-1 receptor and PD-L1 and PD-L2 ligands to restore T-cell activation, which may play a role in helping the body fight cancer.8,10 PD-1=programmed death 1; PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2.

References: 1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 2. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 3. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. 4. Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway.

Nat Rev Immunol. 2002;2(10):735-747. 5. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 6. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111(7): 3635-3643. 7. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 8. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 9. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation.

Nat Immunol. 2001;2(3):261-268. 10. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Proc Natl Acad Sci U S A. 2002;99(19):12293-12297.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at www.pd1pathway.com.

Š2014 Bristol-Myers Squibb Company. All rights reserved. ONCUS14UB00018-01-01 01/14 Printed in USA.

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REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

In Update, Tasquinimod Continues To Prolong PFS in Metastatic CRPC From Clinical Cancer Research

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ong-term results evaluating the effects of tasquinimod (Active Biotech) in men with metastatic castration-resistant prostate cancer (mCRPC) showed prolonged progression-free survival (PFS) and improved overall survival (OS).

Two hundred and one patients were enrolled in this randomized doubleblind, Phase II clinical trial. Treatments consisted of a once-daily oral dose of tasquinimod (up to 1.0 mg; n=134) or placebo (n=67) following a four-week titration period. Doubleblind treatment at tolerated levels continued for up to six months.

Tasquinimod is an oral immunomo-

dulatory, antiangiogenic and antimetastatic agent that targets S100A9 (MRP-14), an immunomodulatory protein expressed in bone. The authors had earlier determined that tasquinimod slowed disease progression. The researchers, headed by A.J. Armstrong, MD, of Duke Cancer Institute, recently presented updated findings on safety and long-term survival in Clinical Cancer Research (2013;19:6891-6901, PMID: 24255071).

The most common adverse events (AEs) reported in the tasquinimod group were fatigue (29%), nausea (27%) and constipation (25%). Men older than age 75 years were at higher risk for AEs such as decreased appetite or fatigue, whereas patients younger than 75 years were

EXPERT INSIGHT C.A. Stein, MD, PhD Arthur & Rosalie Kaplan Chair in Medical Oncology Deputy Director of Clinical Research Department of Medical Oncology City of Hope Duarte, California

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asquinimod is a quinoline-3-carboxamide that is stated to have antiangiogenic, immunomodulatory and antimetastatic properties.

It was investigated in a multicenter, randomized Phase II study of men with minimally symptomatic (i.e., not being treated with narcotics) CRPC. The end points were six-month PFS and overall PFS. Both of these end points were found to be highly significantly improved.

In the current work, various biomarker correlates of tasquinimod efficacy, in addition to long-term OS (a secondary end point), were also examined. However, for marketing approval by the FDA, the most critical end point will probably be OS, rather than PFS. In a subsequent, ongoing Phase III trial, patients are being treated with tasquinimod before being treated with docetaxel. However, as we have already seen in a similar trial with orteronel (TAK-700), demonstrating increases in OS in this cohort of patients,

despite extremely promising Phase II data, may be a high bar to meet. In fact, even abiraterone in this patient cohort did not meet its primary OS end point (although it was awarded FDA approval on the basis of favorable PFS data).

The OS of patients in this cohort treated with enzalutamide has also recently been evaluated: Despite the five-month OS prolongation in post-docetaxel patients, OS in the earlier group of predocetaxel patients was prolonged by only about 2.5 months, possibly because of the relatively large number of recently approved anti–prostate cancer drugs to which patients can now cross over.

Thus, any new anti–prostate cancer drug, such as tasquinimod, must be added to the end of an increasing pipeline of new drugs, potentially further diluting the OS data.

Additionally, the OS data in the Phase II tasquinimod intent-to-treat patient population is perhaps not as robust as that accumulated by either abiraterone or enzalutamide in their respective

at higher risk for musculoskeletal disorders such as back pain. Most AEs reported were less severe, at grades 1 or 2.

Survival data were collected for a median of 37 months. Median OS was 33.4 months for the tasquinimod group and 30.4 months for the placebo group, findings that were similar to previous reports. In men with bone metastases (n=136), the median OS was 34.2 months in the tasquinimod treatment group and 27.1 months in the placebo group. The authors suggested that significant eventual crossover by placebo patients (41 of 67) and an imbalance in baseline clinical characteristics may have affected OS results.

Biomarker studies also were performed on study participants. Baseline

and treatment levels of known mCRPC prognostic biomarkers, including C-reactive protein, lactate dehydrogenase (LDH), bone alkaline phosphatase (BAP), thrombospondin-1 (TSP-1), transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF)-A and VEGF-C, were collected and analyzed for tasquinimod efficacy. Favorable BAP and LDH results indicated an effect on bone and tumor biology, suggesting a delay in the progression of tumor in bone with the administration of tasquinimod, while not affecting prostate-specific antigen (PSA). Such a nonassociation with PSA suggests that tasquinimod may operate in the tumor microenvironment and may not be prostate cancer–specific.

Levels of various biomarkers below the median value, including thrombospondin-1, TGF-β1, BAP and VEGF-C, were … associated with improved OS in the tasquinimod-treated versus placebo-treated patients. trials. Although patients treated with tasquinimod did survive longer than placebo-treated patients (33 vs. 30 months), the P value was only 0.49 (not significant) because the survival curves overlapped until only 38 and 18 patients remained alive in the treatment and placebo arms, respectively. This means that some 72% of the tasquinimodtreated patients appeared to derive no OS benefit from this drug.

Nevertheless, subsets of patients could be identified that did show benefit. These included patients with PSA on day 1 of less than 24 (this was the strongest predictor of PFS and OS), PSA doubling times greater than 4.4 months, patients with LDH less than 204, and patients with BAP less than 21 (i.e., those patients tending to have less aggressive disease). Furthermore, levels of various biomarkers below the median value, including TSP-1, TGF-β1, BAP, and VEGF-C, were also associated with improved OS in the tasquinimod-treated versus placebo-treated patients.

The trial also provided a suggestion

of increased survival in the group with bone metastases. However, even in this cohort of patients, the OS curves overlapped for two years of treatment ( =0.19), and 42% of the patients in (P this group derived no benefit from tasquinimod treatment. This is concerning for the future clinical viability of this drug, especially given the data from the newer “hormone” therapies directed at the testosterone–androgen receptor nexus. On the other hand, tasquinimod appears to be well tolerated, with only small numbers of grade 3/4 events (5% increased lipase, 4% muscle weakness) observed in treated patients. Nevertheless, the number of patients in this Phase II study is relatively small, and only appropriately statistically powered, randomized Phase III data, as will be obtained from the ongoing trial accruing patients with bone metastases, can adequately address the question of OS. Dr. Stein reported no relevant financial disclosures.

More REVIEWS and COMMENTARIES from City of Hope Find additional, Web-exclusive expert commentaries on important published studies at

ClinicalOncology.com

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

Sunitinib Hepatocellular Cancer Trial Ended for Futility From Journal of Clinical Oncology

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trial comparing outcomes of patients with hepatocellular cancer (HCC) treated with sunitinib (Sutent, Pfizer) with outcomes of those treated with sorafenib (Nexavar, Bayer/Onyx) was terminated for futility when overall survival (OS) with sunitinib proved inferior.

The current recommended treatment for unresectable HCC is sorafenib, a vascular endothelial growth factor (VEGF) inhibitor. Investigators sought to compare sorafenib with sunitinib, which has similar properties, in an international, open-label, Phase III trial. Patient selection focused on Asia; 75.6% of enrolled study participants (812 of 1,074) originated from nine Asian countries.

EXPERT INSIGHT Vincent Chung, MD Associate Clinical Professor Medical Oncology City of Hope Duarte, California

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CC is a leading cause of death worldwide, with the incidence continuing to increase.1 Caught in the early stages, cure is still possible with liver transplant or resection, but in the advanced stages treatments are only palliative. Sorafenib was the first molecular targeted therapy to improve survival in patients with advanced HCC. By targeting the Raf-MEK-ERK signaling pathway, VEGF receptors 1, 2 and 3 and platelet-derived growth factor receptor-β, which play an important role in the pathogenesis of HCC, survival was improved by three months over placebo.2 Because HCC is a vascular tumor and high VEGF expression has been associated with a poor prognosis, several studies have been conducted targeting VEGF. This study, published by Cheng et al, evaluated whether sunitinib was superior or equivalent to sorafenib.

Sunitinib is an oral multikinase inhibitor targeting VEGFR1, VEGFR2, PDGFR-a/b, c-kit, FLT3 and RET. Prior trials tested multiple dosing schedules with encouraging results, but toxicity was limiting. This Phase III trial used continuous daily dosing of 37.5 mg; more than 1,000 patients were randomized between the two arms. Surprisingly, the trial was terminated early due to futility and safety reasons. Across all

Among the other patient characteristics in the study were the presence of esophageal varices in 27.7% of those in the sunitinib group versus 28.7% in the sorafenib group; hepatitis B virus infection in 54.7% versus 52.9%; hepatitis C virus (HCV) infection in 21.3% versus 21.9%; vascular invasion and/or extrahepatic spread in 78.9% versus 76.3%; and underlying cirrhosis in 50.0% versus 45.4%, respectively.

The international group of investigators, whose lead author was AnnLii Cheng, MD, published its findings in the Journal of Clinical Oncology (2013;31:4067-4075, PMID: 24081937).

There were 544 patients in the sorafenib arm (400 mg twice daily) and 530 in the sunitinib arm (37.5 mg once daily). The

primary end point was OS; secondary end points were progression-free survival, time to progression (TTP) and safety.

Median OS was 7.9 and 10.2 months for those in the sunitinib and sorafenib arms, respectively (hazard ratio [HR], 1.30; one-sided P=0.9990, two-sided P=0.0014). Median OS for patients from Asia was 7.7 and 8.8 months with sunitinib and sorafenib, respectively (HR, 1.21; one-sided P=0.9829), whereas median OS for patients enrolled from non-Asian countries was 9.3 versus 15.1 months with sunitinib and sorafenib, respectively (HR, 1.64; 95% confidence interval, 1.20-2.26; P=0.9964).

TTP was 4.1 months with sunitinib versus 3.8 months with sorafenib (HR 1.13; one-sided P=0.8312; two-sided

P=0.3082). TTP rates differed between Asian and non-Asian populations, as well as in subgroups of patients with HBV and HCV. Adverse events (AEs), primarily of grades 1 and 2, were frequent in both groups. Nonetheless, grade 3 and 4 AEs occurred in 432 (82.1%) of patients receiving sunitinib and 402 (74.2%) of patients receiving sorafenib.

The most common AEs of grades 3 and 4 were thrombocytopenia (29.7%) and neutropenia (25.7%) in the sunitinib group and hand–foot syndrome (21.2%) in the sorafenib group. Treatment discontinuations caused by AEs were recorded in 13.3% of patients in the sunitinib arm and 12.7% of patients in the sorafenib arm.

groups, survival was worse in the sunitinib group, with non-Asian patients faring particularly poorly when compared with patients who were administered sorafenib. Overall, the trial was well conducted, accruing patients from 23 countries (nine Asian countries).

Between the two arms, differences were seen in the patient characteristics, with Asian patients and patients in the sunitinib group having more advanced disease. In non-Asian patients treated with sorafenib, 68.7% had Barcelona Clinic Liver Cancer stage C disease compared with 78.1% in the sunitinib-treated group, but this could not account for such a large difference in survival: 15.1 versus 9.3 months, respectively. As seen in previous studies, the behavior of HCC in Asian and nonAsian patients is different and exhibits a different biology. In the Asia-Pacific study, sorafenib still improved survival over placebo, with median OS increasing from 4.2 to 6.5 months ((P=0.014).

However, this OS was much shorter than demonstrated in the results of the SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol) trial, which improved survival from 7.9 to 10.7 months (P ( <0.001).3 If we look at the etiology of the cancer, we find that a majority of patients in Asian countries develop HCC from hepatitis B virus infection compared with hepatitis C virus (HCV) infection. In tissues infected with hepatitis C, there is activation of the Raf-1-MEK-ERK pathway leading to cell proliferation. Sorafenib inhibits the Raf-1 kinase at nanomolar concentrations, giving it a comparative advantage over sunitinib, which does not hit this target. Additional research is being proposed to evaluate the effects of sorafenib on HCV replication

(ClinicalTrials.gov: NCT01849588).

The drive for personalized medicine has led to an explosion of knowledge about the signaling pathways important for HCC pathogenesis. In addition to VEGF, it has been determined that fibroblast growth factor (FGF) receptor also is an important driver of angiogenesis. Although other clinical trials with VEGF inhibitors have met a fate similar to that of sunitinib in HCC, there was particular interest in brivanib, a smallmolecule inhibitor of VEGF and FGF. The BRISK-FL study (Brivanib Study in HCC Patients at Risk—First-Line) randomized patients with advanced unresectable HCC to either brivanib or sorafenib. The primary end point of OS noninferiority was not met and brivanib was less well tolerated compared with sorafenib although both agents had similar antitumor activity. The discontinuation rate due to AEs was 33% for sorafenib and 43% for brivanib. In the subset analysis, there was also a slightly longer survival in HCV patients treated with sorafenib, which may reflect the importance of Raf inhibition.4 For patients failing or being intolerant of sorafenib, the BRISK-PS (Brivanib Study in HCC Patients at Risk—Post Sorafenib) study randomized patients in a 2:1 fashion to either brivanib or best supportive care. Unfortunately, brivanib did not improve OS.5 As we learn more about potential driver pathways leading to cell proliferation, clinical trials of rational combinations are being conducted. AZD6244 in combination with sorafenib was tested in HCC but, as we have seen with other combinations of small-molecule inhibitors, the toxicities can be quite significant, limiting their use. In the first dose level of the trial, AZD6244

at 50 mg twice daily and sorafenib at 400 mg twice daily, there were two dose-limiting toxicities in six patients.

The recommended Phase II dose was 75 mg daily of AZD6244 and 400 mg twice daily of sorafenib (ClinicalTrials. gov: NCT01029418).

Many other VEGF inhibitors have been tested with varying degrees of activity, but so far, none has been able to surpass sorafenib. Going forward, we need to establish biomarkers that can help guide treatment decisions to maximize effectiveness while minimizing toxicities.

References 1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer.

2010;127:2893-2917, PMID: 21351269.

2. Llovet JM, Ricci S, Mazzaferro V, et al.

Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390, PMID: 18650514.

3. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25-34, PMID: 19095497.

4. Johnson PJ, Qin S, Park JW, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.

J Clin Oncol. 2013;31:3517-3524, PMID: 23980084.

5. Llovet JM, Decaens T, Raoul JL, et al.

Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol.

2013;31:3509-3516, PMID: 23980090.

Dr. Chung reported no relevant financial disclosures.

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PAY-FOR-DELAY continued from page 1

AstraZeneca and Barr revived a weak patent that the court had already deemed invalid, and that the companies had created a monopoly on tamoxifen that maintained the artificially high price of the drug and prevented competition from other generic manufacturers for almost a decade.

Ultimately, the district court dismissed the class action case against AstraZeneca and Barr, a decision that was upheld on appeal in 2006. This outcome of the tamoxifen trial, along with a 2005 case examining a pay-for-delay deal for the hypokalemia drug K-Dur 20 (FTC v Schering-Plough Corp.), has made a significant mark on the pay-for-delay landscape. The courts’ decisions in both these cases reflected a broad interpretation of the patent right, rejecting a company’s liability for engaging in a reverse payment agreement and insulating the patentee from competition, regardless of how likely the patent would have been overturned in court.

“Tamoxifen and Schering-Plough opened the door to additional reverse payment agreements, by seeming to give a green light to the deals,” said Scott Hemphill, JD, PhD, a professor of law at Columbia Law School in New York City, who specializes in antitrust law.

The Federal Trade Commission (FTC) uncovered a surge in pay-for-delay deal agreements after 2006: 14 in 2007, 16 in 2008, 19 in 2009, 31 in 2010, 28 in 2011 and 40 in 2012.

Although tamoxifen is the most notable example of pay-for-delay in the cancer arena, branded cancer drugs are especially attractive targets for these deals.

“Pay-for-delay deals are particularly important in the cancer market because the potential revenue derived from even limited additional patent protection is enormous,” said Rena Conti, PhD, an assistant professor of pediatric hematology/oncology at the University of Chicago.

Not only do these branded cancer drugs garner annual sales in the hundreds of millions of dollars, but current regimens for common cancers require chemotherapy cocktails, making many of these agents a backbone for treating breast, colorectal and lung cancers.

“Therefore, the market demand for these drugs is stable and likely remains so even when they lose patent protection,” Dr. Conti said. “This pattern is different than what is observed in the non–specialty drug markets where, oftentimes, a drug’s impending loss of patent protection results in physicians shifting away from its use toward newer patent-protected drug substitutes.”

Origins of Pay-for-Delay Pay-for-delay agreements are likely an unanticipated consequence of the 1984 Drug Price Competition and Patent Term Restoration Act, known as the Hatch-Waxman Act. The Hatch-Waxman Act was enacted to encourage competition among drug manufacturers by providing incentives for generic drug makers to challenge brand-name pharmaceutical patents, especially weak ones, and to bring lowercost versions of brand-name drugs to market before patent expiry.

This act makes generic entry particularly desirable because the first generic manufacturer to file a challenge claiming the patent is invalid or not infringed is eligible for 180 days of marketing exclusivity. During that period, only the “first filer” generic company and the brand-name firm are in the market. Because generic drugs cost significantly less than their brandname counterparts, generic companies often dominate the market and earn their greatest profits during this exclusivity period. Since enactment of the HatchWaxman Act, the use of generic drugs has exploded, growing from 20% of prescriptions in 1984 to about 84% in 2013, according to the Generic Pharmaceutical Association (GPhA).

Prior to Hatch-Waxman, manufacturers were required to conduct clinical trials on a new generic product, an expensive and time-consuming process that severely limited generics from entering the market. Hatch-Waxman, however, only requires that generic manufacturers file an Abbreviated New Drug Application (ANDA) with the FDA, in which the generic formulation must demonstrate bioequivalence to the brand-name drug and the company must confirm that its generic drug does not violate any existing patents.

Hatch-Waxman permits a generic manufacturer to challenge a patent immediately after a new drug comes to market. For instance, just four months after

The Federal Trade Commission has uncovered a surge in pay-for-delay deal agreements: 14 in 2007, 16 in 2008, 19 in 2009, 31 in 2010, 28 in 2011 and 40 in 2012.

by the

numbers: Pay-for-Delay

$98 billion | FTC’s estimate of how much brand-name drug companies have earned from delayed generics

$3.5 billion | Additional cost for American consumers annually as a result of pay-for-delay agreements

$16,200 | Additional cost per drug per patient over the average five-year duration of a pay-for-delay deal

$11 billion | Savings to federal health care plans over the next 10 years if pay-for-delay agreements are banned, according to the White House

‘Pay-for-delay deals are particularly important in the cancer market because the potential revenue derived from even limited additional patent protection is enormous.’

—Rena Conti, PhD tamoxifen’s patent was awarded in August 1985, Barr filed an ANDA requesting the FDA’s approval to market its generic version of tamoxifen.

There are several avenues by which a generic company can challenge a patent, but the most popular method is under paragraph IV of the act. Paragraph IV states that a generic company can claim a patent is either invalid or its generic product does not infringe on any relevant patents. Such challenges are almost always met with a lawsuit from the brand-name drug company.

“This pattern—launch, challenge, sue—is frequent for major drugs, and it has become the norm for the best-selling drugs,” Dr. Hemphill said.

A drug with weaker patents faces a significantly greater likelihood of being challenged by a generic manufacturer (J ( Empirical Legal Stud d 2011;8:613-649).

In April 1992, the district court declared tamoxifen’s patent invalid because the company that obtained the patent had withheld vital test results from the United States Patent and Trademark Office, revealing potentially dangerous hormonal effects of the drug.

“One main concern with the current patent approval process is that there are many stages at which applicants can try to get a patent approved and they may be wearing down patent examiners,” said Michael Carrier, JD, a distinguished professor of law at Rutgers University in Camden, N.J., and a leading expert in antitrust and patent law. “There are a lot of patents that should not have been issued by the Patent Office in the first place.”

When a patent is or likely will be overturned, pharmaceutical companies may find it financially worthwhile to pay generic manufacturers to delay entry into the market. Sales of brand-name drugs decline significantly after generic counterparts enter the market because generics typically cost 10% to 15% of the brand-name drug’s price. Additionally, a brand-name drug company can lose up to 90% of its market share. For instance, Nolvadex’s U.S. sales totaled $265 million in 1992 and $442

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

A pay-for-delay agreement could explain why a generic version of the injectable oncologic oxaliplatin (Eloxatin, Sanofi-Aventis) has not yet come to market. million in 2001 before patent expiry, but after, sales sank to $114 million in 2005.

The extent to which pay-for-delay has affected cancer drugs is difficult to track because the details of the deals are rarely publicly disclosed. A pay-fordelay agreement could explain why a generic version of the injectable oncologic oxaliplatin (Eloxatin, Sanofi-Aventis) has not yet come to market. In June 2010, Sanofi-Aventis settled a U.S. patent lawsuit with four generic drug makers after a court ruled that their challenge did not infringe on the drug patent. The agreement detailed that the generic manufacturers would hold off selling generic products until August 2012. Although the remaining terms of the settlement were confidential, The Wall Street Journal quoted Fiske analyst Peter Cartwright saying, “It looks like another pay-for-delay deal, but it’s not clear who is paying what.”

Pay-for-Delay Controversy The controversy over pay-for-delay centers on whether or not these deals violate antitrust law, maintain high drug prices, and decrease patients’ access to affordable medications.

According to analyses from the GPhA, pay-fordelay agreements have allowed hundreds of generics to come to market years before the brand patent’s expiration, translating into billions of dollars in savings for consumers and the health care system. Specifically, for tamoxifen, Barr estimated that selling the AstraZeneca-made generic version of tamoxifen from 1994 to 2002 resulted in $200 million in savings.

Others argue that upholding brand-name drug patents helps fuel future innovation. “Intellectual property is absolutely vital for incentivizing the production of new goods,” said Richard Manning, PhD, a partner at the economic consulting firm Bates White, in Washington, D.C. Clinical Oncology News contacted representatives from Teva Pharmaceuticals (which acquired Barr in 2008), AstraZeneca and defendants in the tamoxifen case for comment, but did not receive replies.

Opponents of these agreements argue that the strategy prolongs the life of weak patents, delays generic entry and maintains high brand-name drug prices.

“Pay-for-delay deals undermine the competition that the Hatch-Waxman Act was designed to foster,” Dr. Hemphill said. “When a branded drug maker pays the generic firm to abandon early entry, the result is higher prices for a longer period of time.” For cancer drugs, prices drop 50% or more after generic entry.

Additionally, as Dr. Conti pointed out, for every generic drug that enters the market “early,” there are many that do not. Take the multibillion-dollar blockbuster epoetin alfa (Epogen, Amgen). This anemia drug, approved by the FDA in June 1989, is 24 years into its 27-year patent life.

The FTC estimates that brand-name drug companies have earned about $98 billion in total sales of drugs for which the generic versions were delayed, and pay-for-delay agreements cost American consumers $3.5 billion annually overall on prescription drugs. On average, a brand-name drug costs an individual and a health plan an extra $270 per month, which when extended over the average five-year duration of a pay-for-delay deal, amounts to $16,200 per drug per patient.

The White House has called for a ban on these deals in its 2014 fiscal year budget proposal, stating that restricting pay-for-delay agreements would “increase the availability of generic drugs and biologics” and deliver $11 billion in savings to federal health care programs over the next 10 years.

“Perhaps most importantly,” Mr. Carrier said, “overturning an invalid patent and allowing a generic to come to market may permit patients to take a lifesaving drug they couldn’t otherwise afford.”

The Future of Pay-for-Delay Legal rulings strongly affect the future of pay-fordelay deals. Most recently, a Supreme Court decision in a reverse payment case involving the testosterone patch Androgel (Solvay Pharmaceuticals) may alter the pay-for-delay environment. In June 2013, the Supreme Court discarded lower-court rulings that deemed these agreements automatically legal, and instead declared that reverse payments can violate antitrust laws. ““FTC v Actavis changes the landscape in a fundamental way by establishing that a large and otherwise

unexplained payment is best understood as an illegal payment to avoid competition,” Dr. Hemphill said.

The majority opinion held that it is not necessary to re-litigate the patent merits because one can infer a patent is weak from the size of the agreement payment.

“The Supreme Court makes clear that payments and compensation can come in many forms, and value transferred from brand to generic that forestalls [generic] entry warrants scrutiny,” Ms. Hart said.

However, the vagueness of what constitutes compensation may be problematic because it creates an opportunity for agreements to take less obvious forms that may pass scrutiny in court.

“Going forward, one important issue will be to recognize variants of the pay-for-delay theme as they arise,” Dr. Hemphill noted. “Compensation can take many forms, and the challenge for courts will be to properly recognize these payments when they occur.”

The FTC estimates that pay-for-delay agreements cost American consumers $3.5 billion annually overall on prescription drugs.

For instance, payments may not be direct cash transfers but could come in the form of unrelated services or an agreement that the brand-name company will not launch its own generic drug during the company’s 180-day exclusivity period.

“The Supreme Court decision still leaves a lot of open issues, which we will be hashing out for years to come,” Mr. Carrier said.

Several blockbuster cancer drugs are worth watching after the Supreme Court decision, including imatinib (Gleevec, Novartis), pemetrexed (Alimta, Eli Lilly), gemcitabine (Gemzar, Eli Lilly) and dasatinib (Sprycel, Bristol-Myers Squibb). Although no evidence points to pay-for-delay deals for these drugs at present, the potential benefit for branded drug manufacturers to enter into these agreements for such high-profile cancer drugs is enormous.

“If patent expiration is successfully delayed for these drugs by such deals, [then] patients, physicians and insurers will clearly pay more than expected,” Dr. Conti said.

—Victoria Stern

LOOK AHEAD Next month’s issue of Clinical Oncology News will feature continuing in-depth coverage of the San Antonio Breast Cancer Symposium and the annual meeting of the American Society of Hematology

—————————— Expert Roundtable —————————— Upcoming issues of Clinical Oncology News will also feature an expert editorial roundtable on the state of palliative care in America, including clinical experts from ASCO, The Institute for Palliative Medicine at San Diego Hospice, Johns Hopkins and Duke University, among others.

Look for it!

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BISPHOSPHONATES continued from page 1

patients in these trials has not been in vain. We have finally defined a new addition to standard treatment,” said Robert Coleman, MBBS, MD, a professor of medical oncology at the University of Sheffield in Sheffield, England, who presented the study (S4-07). “The incremental benefit is at least as large as we have seen with most of the agents we use at the moment, aromatase inhibitors, taxanes, et cetera.”

He recommended use of either zoledronic acid at least every six months or, in countries where available, daily oral clodronate. He pointed out that there is no data with the weekly dose of oral bisphosphonates used to treat osteoporosis, so these drugs and schedules cannot be recommended.

For the past 15 years, various studies have investigated whether bisphosphonates can exert an anticancer effect in patients with breast cancer. Some studies showed a clear benefit. Others did not, but hinted at a benefit in subsets of patients. A number of hypotheses, however, emerged: Bisphosphonates might only exert anticancer benefits in women with low levels of estrogen, and only on distant metastases rather than local recurrences or contralateral disease. The

scientific rationale for bisphosphonates as an anticancer agent lies in the fact that osteoclasts and osteoblasts are critical to the development of metastases (Figure).

In the SABCS study, the Early Breast Cancer Trialists’ Collaborative Group conducted a meta-analysis of data from all randomized trials comparing the use of bisphosphonates in the adjuvant setting of breast cancer versus no bisphosphonate or placebo. The meta-analysis included 36 trials involving roughly 20,000 patients. Subgroup analyses included outcomes by site of recurrence, site of first distant metastasis (bone vs. not bone), menopausal status (pre-, periand postmenopausal), type of bisphosphonate (aminobisphosphonate or clodronate), and drug schedule (advanced cancer or bone protection). Aminobisphosphonates included mainly zoledronic acid (65%), some oral ibandronate (24%) and oral pamidronate (8%), and a few oral residronate and oral alendronate.

In postmenopausal women, adjuvant bisphosphonates reduced the risk for bone recurrence by 34% (P ( =0.00001) and reduced the risk for breast cancer death by 17% ((P=0.004). The effect was somewhat more pronounced in patients receiving an anticancer dose of the drug,

The Vicious Cycle of Bone Destruction

rather than just an osteoporosis dose.

The benefit was seen in patients regardless of estrogen-receptor status, node status or whether the patients also were receiving chemotherapy. In postmenopausal women, bisphosphonates had no effect on deaths not related to breast cancer, contralateral breast cancer or locoregional recurrence. In premenopausal women, the drugs had no significant effect on any disease outcomes.

the risk for metastases,” said Dr. Rugo.

“The meta-analysis was very, very useful and really gives us an idea that there is a group of patients who are in menopause where bone turnover is a really big deal, and you can possibly reduce the incidence of bone metastases with bisphosphonates.”

“My take on it,” she continued, “is that I use it in patients in menopause who are having bone loss, because that is

For the past 15 years, various studies have investigated whether bisphosphonates can exert an anticancer effect in breast cancer patients.

“The cumulative data are becoming more and more convincing,” said Kent Osborne, MD, the director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston. He suspected the study would change practice at his center.

Hope Rugo, MD, the director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, said clinicians are still questioning whether or not to change their practice based on the data.

“I think we have quite a bit of background data that suggests that at least for a subset of patients, bisphosphonates play a role in reducing or delaying

what the approved indication is. I think if you had a patient who was identical to the ABCSG-12 trial population—young, on ovarian suppression, hormone therapy and no chemo—then I would use a bisphosphonate. Outside of that, it is really hard to know. However, based on this data, I would consider adjuvant bisphosphonates for women with higher-risk disease.”

—Kate O’Rourke Dr. Coleman has received speaker fees from Bayer and research funding from Novartis.

Dr. Osborne has been a consultant/advisor for AstraZeneca, Genentech and Novartis.

Dr. Rugo disclosed research funding from AstraZeneca and Novartis.

Bisphosphonates Embed in Bone and Interrupt the Cycle

Figure. The scientific rationale for bisphosphonates as an anticancer agent lies in the fact that osteoclasts and osteoblasts are critical to the development of metastases. Tumor cells secrete factors that stimulate osteoclast differentiation and maturation, and cancer cells directly interact with osteoclast precursors.

Tumor cells also secrete various growth factors that increase bone cell function and, through the release of RANK ligand, both enhance bone destruction and the release of bone-derived factors that can stimulate tumor growth. Bone resorption agents can inhibit osteoclasts and block the release of growth factors and cytokines from bone that create the fertile environment for cancer growth.

BMP, bone morphogenetic protein; Ca, calcium; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL, interleukin; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor

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From Private Practice to Hospital Employee Oncologists describe loss of control as a major difficulty, among other problems Boston—Across the United States, private oncology practices are being snapped up by hospitals. So, what is it like to go from being an oncology business owner to a hospital employee? At the recent National Oncology Conference, two oncologists discussed the pros and cons.

“There are a lot of pitfalls. The most important thing is to try to remain focused on patient care,” Terrence Cescon, MD, said. He was the executive vice president of the nine-physician practice Berks Hematology-Oncology Associates, in Reading, Pa., before it was sold to Reading Health Care System.

Dr. Cescon became a hospital employee in January 2013. Given the chance, he would not do it again, and he likened being a hospital employee to being a raindrop in an ocean. “You have no say, no control, over anything,” he said.

According to Dr. Cescon, Berks sold because of political pressure, not fiscal woes. “Our practice was doing well.

I think the partners were getting wary about what the future was going to hold.

We got a lot of pressure from the [hospital],” he said. He cautioned about letting a hospital pay for a private practice evaluation. Berks did this, and Dr. Cescon believes the practice evaluation was erroneous.

Dr. Cescon has been overwhelmed by the number of hospital staff issuing edicts on administrative day-today operations and on patient care. For example, he no longer is able to give patients copies of their pathology and laboratory reports, which was a routine practice at Berks. Accustomed to answering to one president of his private practice, he found he suddenly had “aa million o different d e e t bosses.” bosses.

According to Dr. Cescon, Reading changed numerous aspects of Berks when it acquired the practice, including the computers, electronic medical records and processes used to ensure patient identification. “We had a lot of processes in place that worked extremely well,” he said. “They messed with everything. … You don’t make decisions anymore. If you are a physician and you want to buy a widget, you have to go and get permission. It requires an act of Congress.”

Physicians transitioning to a hospital setting also may lose control over staff.

“One of the things you have [the] advantage of in private practice is you can hire good people and let them do their job and get out of their way. When the hospital comes in, their criteria are different. We had recent layoffs, based upon seniority, and in many cases, those who have the lowest seniority might have been the best people,” Dr. Cescon said. “All our staff is slowly being picked away.”

Hyatt “Tracy” DeGreen III, DO, the managing partner of a four-physician practice, Lancaster Cancer Center in Lancaster, Pa., agreed that oncologists making the transition to hospital employees need to prepare themselves for loss of control. “You definitely lose autonomy,” he said. “From my previous experiences, it is more difficult to practice medicine when there are so many to answer to. In my practice, I answer only to the patient and the insurances.”

Before practicing at Lancaster Cancer Center, Dr. DeGreen worked at Penn State Hershey Medical Center; he still treats some patients at local hospitals. “I treat many patients at the local hospital, and it is much more difficult in many a y ways, ways,” hee said. sa d. For o example, e a p e,

insurances accepted by a hospital may not be accepted by the outpatient infusion center. Patients arrive for appointments, expecting to be seen and treated, and are told that their insurance is not taken at the infusion center. According to Dr. DeGreen, Lancaster Cancer Center was recently approached by a hospital and decided not to sell.

Many physicians transitioning to a hospital setting have problems with loss of autonomy, according to a recent white paper on oncologist–hospital integration.

The white paper, “Opportunities and New Realities in Cancer Care,” was the product of an Institute for the Future of Oncology forum involving 40 participants, oncologists and cancer program executives from hospitals, practices and health care systems across the United States.

Forum participants said physicians transitioning to the hospital might have difficulty with the loss of day-to-day control over administrative matters, the need to be accountable to institutional policies and procedures, and the need to meet accreditation requirements for the Joint Commission and the American College of Surgeons. This report also stated that “merging or migrating IT from a physician office setting to a hospital can be an enormous task,” and that patients transitioning to a hospital setting may encounter more time in the waiting room and higher copays.

Dr. Cescon said that in his hospital setting, patient copays have doubled and wait times have increased. Patients also have been inconvenienced by the loss of an outpatient pharmacy. “A hospital is not interested in having an outpatient pharmacy,” Dr. Cescon said. “There iss a certain ce ta convenience co ve e ce factor acto that t at just

One newly minted hospital oncologist found he suddenly had ‘a million different bosses.’

disappears for the patients, because you can’t go and hand them their dexamethasone for the next cycle of chemotherapy.”

Dr. DeGreen agreed that when a private practice transitions to a hospital setting, the loss of a dispensary can have big implications. “It’s very nice to have a dispensary, because patients get the teaching not just from myself but from the pharmacists and nurses,” Dr. DeGreen said.

Studies have shown that when patients buy from mail order companies, education about adverse drug reactions is lacking, and this increases emergency room visits and hospitalizations.

Dr. Cescon also complained that patients were inconvenienced by the loss of a laboratory in their office, which provided lab results in 15 minutes. “Right now, it can take easily an hour for us to get lab-reported data back, so patients just sit there,” he said.

According to Dr. DeGreen, the increased wait times caused by the loss of a laboratory is frustrating but understandable, given that a hospital laboratory is caring for a varied patient base.

One benefit of being affiliated with a hospital is reducing the high cost of drugs. Nonprofit hospitals benefit from 340B pricing. Dr. DeGreen added that it is difficult for private practices to absorb drug costs when a patient cannot pay. Hospitals are in a better position to do this, because they have other profit centers. The Institute for the Future of Oncology white paper concluded that many of the private practices that consolidated “were satisfied with the additional resources and improved operational efficiencies of a hospital.”

Dr. Cescon had several recommendations for private practices considering selling to a hospital: Leave negotiations to the lawyers and get all promises in writing. “When you ask them to put [an item] in writing and they won’t do it, that is because they are not going to keep that promise,” Dr. Cescon said. Even with a contract on paper, however, nothing is set in stone. “Your contract is definitely not guaranteed,” Dr. Cescon added. “The hospital can come back and say, ‘I’m sorry, I know we have a contract but we don’t have the money to pay you, so we are going to have to adjust this contract.’

You can either sign the new contract or you can leave.”

Instead of hospital direct employment, Dr. Cescon recommended that private practices enter into a professional services agreement with a hospital. “That keeps everyone separate enough that physicians are going to be happier,” he said.

—Kate O’Rourke

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

How I Manage ...

Hematopoietic Stem Cell Transplantation In Waldenström’s Macroglobulinemia

W

aldenström’s macroglobulinemia (WM) is defined by the presence of lymphoplasmacytic lymphoma involving the bone marrow, liver, spleen and lymph nodes. A monoclonal immunoglobulin (Ig)M protein is required to distinguish WM from lymphoplasmacytic lymphoma.

Patients can present with markedly elevated IgM levels and infiltration of the bone marrow in excess of 30% yet still not require therapy because they lack symptoms and have preserved marrow function. Conversely, patients can have low levels of IgM protein and minimal clonal infiltration and may still require therapy for complications such as amyloid light-chain amyloidosis, cryoglobulinemia or IgM-associated peripheral neuropathy.

At Mayo Clinic, IgM monoclonal proteins represent 17% of all monoclonal proteins seen, but WM is only 2% of all patients, suggesting a high proportion of patients with IgM proteins are either monoclonal gammopathy of undetermined significance (MGUS) or smoldering WM and are not in need of immediate therapy. The age-adjusted incidence of WM is 5.5 per million persons per year. The risk for transformation of IgM MGUS is 2% annually. Whole-genome sequencing of lymphoplasmacytic cells from WM has identified a sequence variation in chromosome 3p22.2. A single nucleotide change from T to C in the MYD88 gene resulted in a leucine-toproline change at amino acid position 265. MYD88 L265P mutation is found in 90% of patients with WM and should aid in diagnosis of this disease.

Distinguishing between WM and marginal zone lymphoma (MZL) can be challenging. The MYD88 L265P mutation can assist in proper diagnosis of WM in the majority of patients.

It is important to acknowledge that the MYD88 mutation is not specific to WM but also seen in 4% of splenic MZL and 7% of patients with mucosa-associated lymphoid tissue lymphoma. Interestingly, MYD88 mutations are present in IgM MGUS, suggesting the mutation is a precursor or early event but is not the transforming event. The mutation is not found in IgM multiple myeloma (MM).

There has been an explosion of new regimens for the treatment of WM. Hematopoietic cell transplantation (HCT) has been shown to be an effective tool in the management of WM, but questions remain regarding sequencing,

AT A GLANCE • The MYD88 L265P mutation found in 90% of patients with Waldenström’s macroglobulinemia (WM) should aid in diagnosis of this disease.

• The International Prognostic Scoring System for WM (IPSSWM) is an easily applied clinical tool to predict survival outcomes in patients.

• It is the policy at Mayo Clinic to collect and cryopreserve peripheral blood stem cells in all patients with WM who are under the age of 70 years in their first plateau.

• A long unmaintained response is a compelling reason to consider autologous HCT in early relapse for patients with WM. • There is clear evidence of a potent graft-versus-lymphoma effect in WM. • Patients with advanced WM should be encouraged to participate in clinical trials.

timing and the role of allogeneic HCT (alloHCT). This current practice piece is designed to answer questions surrounding the role of HCT in the management of WM.

Is there a role for autologous HCT (autoHCT) in patients with WM who are in first remission?

In view of the large number of effective standard chemotherapeutic regimens available for patients with WM, the majority of published reports deal with its application after an initial relapse. There have been a number of trials that have explored the use of autologous HCT as initial therapy or shortly after induction therapy.

The decision to use early autoHCT is affected by the patient’s age, comorbidities, pace of disease and overall functional status.

The International Prognostic Scoring System for WM (IPSSWM) is an easily applied clinical tool to predict survival outcomes in WM. This prognostic system allocates patients into low, intermediate or high risk based on five features: hemoglobin (<11.5 g/dL), platelet count (<100/mcL), β2-microglobulin (>3 mg/dL), serum monoclonal protein level (>7 g/dL) and age (>65 years). Further refinement of the staging system has been reported where lactate dehydrogenase (LDH) can further stratify high-risk patients. The median survival for high-risk patients with elevated LDH is only 35 months.1 In one study of 12 patients receiving autoHCT as part of first-line therapy, chemo-mobilization was used to reduce the tumor mass. Patients were conditioned with cyclophosphamide (CY) and total-body radiation and then received a B-cell purged graft. Only two of nine evaluable patients achieved a complete response, six relapsed with a

Morie Gertz, MD Roland Seidler Jr. Professor of the Art of Medicine Chair of the Department of Internal Medicine Mayo Clinic Rochester, Minnesota

median of 69 months.2 A second study used R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) followed by CY mobilization and high-dose melphalan. Five patients were in a stable partial response with a median follow-up of 66 months.3 The Myeloma Institute for Research and Therapy reported results on 57 patients who were seen without prior therapy and underwent autoHCT. The median event-free survival (EFS) was 4.9 years.

The median overall survival (OS) was 13.8 years, with 25 of 57 patients relapsefree at the time of the report. The median time to treatment from initial evaluation was 57 days, with transplantation occurring at a median of 9.6 months.4 In multivariate analysis, only an elevated LDH was predictive of EFS. Given these encouraging results using autoHCT in the front-line setting, it seems reasonable to explore this option in a welldesigned clinical trial.

When do I recommend autoHCT in patients with WM? Although no consensus exists, it is the policy at Mayo Clinic to collect and cryopreserve peripheral blood stem cells in all patients who are under the age of 70 years in their first plateau. Because many patients will remain in plateau for a median of four or five years, they would still be eligible for high-dose therapy at the time of first progression.

Our preferred conditioning regimen is BEAM (carmustine, etoposide, cytarabine and melphalan), and we can apply this at the time of biochemical progression before complications develop from relapsed disease, and these patients are conditioned without reinduction chemotherapy because chemosensitivity is retained in the majority of patients.

This technique obviates the need for recollection of stem cells in a patient

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suffering from relapse and reduces the risk for a mobilization failure because collection occurred during stable plateau. One drawback is that some centers have policies that do not permit the long-term storage of autologous stem cells for later use.

Is autoHCT underutilized in patients with WM? A critical analysis of the literature should raise the question as to why HCT would be considered in this disease given the wide number of regimens available, including combinations of rituximab, alkylating agents, purine nucleoside analogs and bendamustine. These agents are all active in the treatment of WM, as are non-chemotherapeutic agents such as everolimus, immunomodulatory drugs, bortezomib, carfilzomib and ibrutinib. Given the availability of these low-intensity chemotherapeutic regimens, why consider HCT to treat WM? Alkylating agents and purine nucleoside analogs increase the risk for large cell transformation and myelodysplasia. Peripheral neuropathy is frequently seen in some of the commonly used regimens for patients with WM. The gene transcription profile of WM resembles chronic lymphatic leukemia more than MM. Unlike MM, WM lacks the typical adverse cytogenetics and is a less kinetically active malignancy than MM. The favorable genetics and the low proliferative rate favor the hypothesis that a single course of myeloablative therapy will produce a deep and durable response; and as a consequence, one can anticipate longer plateaus following transplant in WM than is seen in MM. A long plateau following autoHCT in WM is borne out by the literature. A long unmaintained response is a compelling reason to consider autoHCT in early relapse for patients with WM. There is a low treatment-related mortality, excellent quality of life related to the reduced need for subsequent salvage therapies and appreciable durability.

Do I recommend alloHCT outside of a clinical trial in patients with WM? The consensus opinion of the International Waldenström’s Working Group

Waldenström’s macroglobulinemia: bone marrow aspirate.

The incorporation of reduced-intensity conditioning has reduced nonrelapse mortality in patients with WM and offers the potential for a cure.

Combining transplant with newly developed agents such as ibrutinib offers hope to previously refractory patients. suggests that alloHCT not be undertaken outside of a clinical trial. Unfortunately, the number of available clinical trials is very limited, and the evidence for benefit of alloHCT for appropriately selected patients is strong. There is clear evidence for a potent graft-versuslymphoma effect in WM. A report of 158 patients by Charalampia Kyriakou, MD, PhD, demonstrated an OS of 68.5% at five years and a relapse-free survival of 39.7% at five years, with 34 of the 158 patients having a complete response. As expected, chronic graft-versus-host disease was associated with higher nonrelapse mortality and lower relapse rate. There are clearly patients for whom conventional chemotherapy may no longer be an appropriate option, or young patients with WM in whom the infusion of allogeneic stem cells is justified. The National Comprehensive Cancer Network recommends alloHCT ideally in the context of a clinical trial but acknowledges this may not always be possible.

Is there a role for maintenance therapy following HCT in patients with WM? There have been no completed trials that have looked at the issue of maintenance therapy following HCT in WM. Lenalidomide (Revlimid, Celgene) maintenance therapy after combination chemotherapy and HCT in patients with persistent WM is recruiting patients. With the use of standard therapy, it is common to administer rituximab maintenance therapy on a quarterly basis. In one report, progression-free

survival and OS were longer in patients who received maintenance rituximab.5 However, this was not in a transplanted cohort, and prospective studies are needed to clarify the role of maintenance rituximab in WM.

What are some exciting new agents or strategies being explored for patients with advanced WM? There are many excellent opportunities for patients with advanced WM and they should be encouraged to participate in clinical trials whenever possible. For example, trials with radioimmunotherapy (ClinicalTrials.gov: NCT01678443) and reduced-intensity conditioning regimens (ClinicalTrials.gov: NCT01760655, NCT00005803, NCT01272817) are ongoing. The role of ipilimumab (Yervoy, Bristol-Myers Squibb; ClinicalTrials.gov: NCT01822509) for patients with relapse after donor stem cell transplantation also is being explored. Additionally, trials with carfilzomib (Kyprolis, Onyx; ClinicalTrials.gov: NCT01813227), pomalidomide (Pomalyst, Celgene; ClinicalTrials.gov: NCT0107897), panobinostat (Novartis, ClinicalTrials.gov: NCT01261247); dasatinib (Sprycel, Bristol-Myers Squibb; ClinicalTrials.gov: NCT00608361) and ibrutinib (Imbruvica, Pharmacyclics/Janssen; ClinicalTrials.gov: NCT01614821) are options for patients with advanced disease.

Future Prospects The introduction of plerixafor (Mozobil, Sanofi-Aventis) has increased the

number of patients eligible for autoHCT. Experienced centers have lowered the treatment-related mortality to 1%. The incorporation of reduced-intensity conditioning has reduced nonrelapse mortality in patients with WM and offers the potential for a cure. Combining transplant with newly developed agents such as ibrutinib offers hope to previously refractory patients.

References 1. Kastritis E, Kyrtsonis MC, Hadjiharissi E, et al. Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom’s macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH). Leuk Res. 2010;34:1340-1343, PMID: 20447689.

2. Dreger P, Schmitz N. Autologous stem cell transplantation as part of first-line treatment of Waldenstrom’s macroglobulinemia.

Biol Blood Marrow Transplant. 2007;13:623624, PMID: 17448924.

3. Caravita T, Siniscalchi A, Tendas A, et al.

High-dose therapy with autologous PBSC transplantation in the front-line treatment of Waldenstrom’s macroglobulinemia.

Bone Marrow Transplant. 2009;43:587-588, PMID: 18978819.

4. Usmani S, Sexton R, Crowley J, Barlogie B. Autologous stem cell transplantation as a care option in Waldenstrom’s macroglobulinemia. Clin Lymphoma Myeloma Leuk.

2011;11:139-142, PMID: 21454216.

5. Treon SP, Hanzis C, Manning RJ, et al.

Maintenance rituximab is associated with improved clinical outcome in rituximab naive patients with Waldenstrom’s macroglobulinaemia who respond to a rituximab-containing regimen. Br J Haematol.

2011;154:357-362, PMID: 21615385.

Series Editor Syed Abutalib, MD Assistant Director, Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America, Zion, Illinois

Coming Soon How I Manage Essential Thrombocytosis

by Ruben A. Mesa, MD Mayo Clinic

17

18

GENETICS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

The genomic revolution

New Tool Gauges Breast Cancer Risk San Antonio—In a cohort of 2,000 patients, next-generation sequencing using a panel of 25 cancer susceptibility genes identified 4.8% more patients with mutations than the 9.3% identified by testing the BRCA1/2 genes alone. The results were presented at the San Antonio Breast Cancer Symposium (PD4-8).

“Identifying individuals with a hereditary cancer risk provides opportunities for early detection, through more intensive screening, and cancer prevention, through the use of prevention medications or prophylactic surgery,” said Nadine Tung, MD, the study presenter and director of the Cancer Risk and Prevention Program at Beth Israel Deaconess Medical Center in Boston.

The 25-gene panel is a precursor to the MyRisk Hereditary Cancer Test, which was launched in September 2013. The 25 genes are associated with eight major hereditary cancers including breast, colon, ovarian, endometrial, pancreatic, prostate, gastric and melanoma. The average price of the test is $3,700.

The new study included two patient cohorts. Cohort 1 included 1,951 prospective cases referred for BRCA1 and BRCA2 testing to Myriad Genetics. There were no Ashkenazi Jews in this cohort. Cohort 2 included 390 patients with hereditary breast and ovarian cancer history at Beth Israel Deaconess Medical Center who previously tested negative for BRCA1 or BRCA2. Some patients in this latter cohort had Ashkenazi ancestry.

Ninety-one percent of patients in cohort 1 and 97% of patients in cohort

2 had breast cancer. Of the patients in cohort 1, 9.3% had a mutation in BRCA1 or BRCA 2 and 4.8% of patients had a mutation in a gene other than BRCA1/2. In cohort 2, 4.4% had a mutation in at least

Matthew Ellis, MB, PhD, the director of the Breast Cancer Program at the Washington University School of Medicine in St. Louis, who was not involved with the work, said the study shows

The typical predictors of BRCA1/2 mutations, such as age at breast cancer diagnosis and family history of breast and ovarian cancer, did not appear to predict for mutations in genes other than BRCA1/2. one of 23 genes other than BRCA1/2. The most common mutations in genes other than BRCA1/2 were CHEK2 (31.8%), NBN N (14.5%), ATM M (12.7%) and PALB2 (12.7%). At least one variant of unknown significance was found in 44% of cohort 1 and 45.4% in cohort 2.

The typical predictors of BRCA1/2 mutations, such as age at breast cancer diagnosis and family history of breast and ovarian cancer, did not appear to predict for mutations in genes other than BRCA1/2. There was a trend toward increased prevalence of mutations in genes other than BRCA1/2 in patients with multiple breast cancers ((P=0.061).

“Factors that predict for BRCA1/2 mutations do not seem to predict for mutations in other genes,” said Dr. Tung. “It may well be that the cancer spectrum and phenotype are different for mutations in each gene.”

that BRCA1 and 2 remain the dominant causes of hereditary breast cancer and that testing the other 23 genes unearthed only a few percent of patients who wouldn’t have been identified with BRCA1/2 testing.

“What that says is that all of these other causes are relatively rare, and because they are rare, we actually don’t have very good information on key issues that are used in clinical decision making like penetrance. Penetrance is the likelihood that you will develop cancer if you have inherited the allele,” said Dr. Ellis. “We know the penetrance is high for BRCA1/2, but it is not really clear how penetrant PALB2 or RAD51C mutations or any of these other genes really are.”

Dr. Ellis had several concerns as the test begins to be used in clinical practice. “We don’t really have good data to

50-Gene Breast Cancer Assay Now Available A

50-gene prognostic breast cancer assay is now available for physicians to use in clinical practice.

The Prosigna Breast Cancer Prognostic Gene Signature Assay, which is based on the PAM50 gene signature, provides a prognostic score on a 0 to 100 scale that correlates with the probability of distant recurrence within 10 years. The test is indicated for postmenopausal women with stage I/II lymph node–negative or stage II lymph node–positive, hormone receptor–positive breast cancer who

have had surgery and locoregional treatment. The test should not be used for patients with four or more positive nodes.

The test classifies tumors into one of four intrinsic subtypes: luminal A, luminal B, HER2-enriched and basal-like. An algorithm combines this information with the gene signature, tumor size and proliferation score to produce a “risk for recurrence score.”

The assay also provides a risk category based on the recurrence score and nodal status; node-negative patients may be

classified as low, intermediate or high risk, whereas node-positive patients are classified as either low or high risk.

The Oncotype DX 21-gene assay is currently a more widely used test to determine the risk for recurrence in these patients. However, a study published July 1, 2013, in the Journal of Clinical Oncology that compared the Oncotype DX recurrence score with the PAM50 risk for recurrence score concluded that the PAM50 provided more prognostic information in these patients with

base practice guidelines yet, so a call for a lot more research is needed,” he said.

Great care needs to be taken so patients are not misinformed as to the strength of the evidence, especially when the information is used to guide decisions about prophylactic therapy, particularly surgery, he added.

“At this point, I’d say that testing with a wider panel, when done under the careful guidance of an experienced genetic counselor who is ready to cope with information on another 23 genes above BRCA1/2, might be modestly helpful in some settings,” said Dr. Ellis. “One shouldn’t overstate its value and one should proceed with caution.”

Dr. Tung agreed that caution is necessary. “The cancer risks associated with several of these genes are not well known and will only become clearer as more mutation carriers are identified and followed. The interpretation of this testing, including the finding of genetic changes of uncertain significance can be complicated and is best conveyed to patients by genetic counselors and clinicians with adequate knowledge in this area,” she said. “I am concerned about both the overestimation of cancer risk that might lead to unnecessary treatment. Equally, I am concerned about a false sense of reassurance to those with a strong family history who test negative for these genes.”

—Kate O’Rourke Drs. Tung and Ellis have no relevant disclosures.

better differentiation of intermediateand higher-risk groups (2013;31:27832790, PMID: 23816962).

The new Prosigna assay received clearance from the FDA in September. It is now available as an in vitro diagnostic kit that can be analyzed by qualified laboratories. Currently, ARUP Laboratories, LabCorp and Quest Diagnostics offer the assay, according to Nanostring Technologies, the assay’s manufacturer.

—Gabriel Miller

Send us your news Clinical Oncology News appreciates news tips and suggestions for coverage from readers.

Write to managing editor Gabriel Miller at gmiller@mcmahonmed.com

Harnessing the Immune System in NSCLC Implications of Emerging Data and Immunotherapeutic Strategies for Personalized Medicine To participate in this FREE CME activity, log on to

Release date: October 1, 2013

www.CMEZone.com

Expiration date: September 30, 2014

Editor

TARGET AUDIENCE

Suresh S. Ramalingam, MD

The target audience for this activity is medical oncologists, hematology/oncology fellows, oncology specialty pharmacists, and other health care professionals involved in the management of individuals with nonsmall cell lung cancer (NSCLC).

Professor of Hematology and Medical Oncology Director, Division of Medical Oncology Emory University School of Medicine Winship Cancer Institute Atlanta, Georgia

EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be able to:

Faculty Julie R. Brahmer, MD

1 Review fundamental concepts of antitumor immune responses in NSCLC.

Associate Professor Johns Hopkins University School of Medicine Baltimore, Maryland

2 Evaluate key efficacy and safety data from ongoing clinical trials evaluating immunotherapeutic strategies for NSCLC, including tecemotide (formerly known as L-BLP25), belagenpumatucel-L, melanoma-associated antigenA3 (MAGE-A3) vaccine, immune checkpoint inhibitors, toll-like receptor agonists, and mycobacterial adjuvant-based agents.

John Nemunaitis, MD Executive Medical Director Mary Crowley Cancer Research Centers Dallas, Texas

Roman Perez-Soler, MD Professor of Medicine Chair, Department of Oncology Montefiore Einstein Center for Cancer Care Chief, Division of Medical Oncology Department of Medicine Deputy Director Albert Einstein Cancer Center Bronx, New York

3 Identify effective immunotherapeutic strategies for early- and advanced-stage NSCLC based on patient and disease characteristics.

4 Recall the ongoing clinical trials evaluating immunotherapeutic approaches for NSCLC to aid appropriate patients for study participation.

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Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

NEJM, JCO, Blood and highlights of oral abstracts from ASH 2013—Part II

5. True or False. 8. True or False. An article published

QUESTIONS

In two studies published in NEJM, all patients with ET or PMF without JAK2 or thrombopoietin receptor gene ((MPL) alteration carried a somatic mutation in the CALR gene, which encodes calreticulin.

1. True or False. A Phase

III randomized study published in The New England Journal of Medicine (NEJM ( M) demonstrated superior progression-free survival (PFS) with rituximab (Rituxan, Genentech)–chlorambucil compared with obinutuzumab (Gazyva, Genentech)–chlorambucil in patients with chronic lymphocytic leukemia (CLL) and coexisting conditions.

6. True

or False.

In the study published Primum non nocere. in NEJM, M a retrospec(First, do no harm.) tive analysis showed that patients with ET True or False. Both obinutuzumab and PMF with CALR exon 9 mutations and rituximab target CD20-positive cells. had a lower risk for thrombosis and longer overall survival (OS) compared with True or False. The Phase III ran- patients harboring JAK2 mutations. domized study published in NEJM M comparing obinutuzumab–chlorambucil with Which of the following mutatrituximab–chlorambucil showed a high- ed genes are observed in patients with er incidence of infusion-related reactions refractory anemia with ring sideroblasts with the former combination in patients associated with marked thrombocytosis with CLL and coexisting conditions.

(RARS-T)? a. JAK2 True or False. Approximately 50% b. MPL to 60% of patients with essential throm- c. CALR bocythemia (ET) and primary myelo- d. SF3B1 fibrosis (PMF) carry a mutation in the e. All of the above Janus kinase 2 ((JAK2) gene.

2.

3.

7.

4.

ANSWERS

1. False. Obinutuzumab was superior

to rituximab when each was combined with chlorambucil in patients with CLL and coexisting conditions. The patients had a median age of 73 years, creatinine clearance of 62 mL per minute and Cumulative Illness Rating Scale score of 8 at baseline. The median PFS—the study’s primary end point—was 26.7, 16.3 and 11.1 months with obinutuzumabchlorambucil, rituximab–chlorambucil and chlorambucil alone, respectively.

Additionally, obinutuzumab–chlorambucil had deeper and longer responses compared with rituximab–chlorambucil and chlorambucil alone.

Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Jan 8.

[Epub ahead of print], PMID: 24401022.

2. True. Rituximab is a chimeric type

1 antibody that kills CLL cells primarily by means of complement-dependent and antibody-dependent cellular cytotoxicity after binding to CD20. Obinutuzumab (also known as GA101) is a humanized,

glycoengineered type 2 antibody also targeted against CD20.

Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Jan 8.

[Epub ahead of print], PMID: 24401022.

3. True. Several prophylactic mea-

sures were implemented during the conduct of the trial (e.g., premedication with glucocorticoids and administration of the first dose of obinutuzumab over a period of two days). An important observation was that all grade 3 or 4 infusionrelated reactions occurred during the first infusion of obinutuzumab but not during subsequent infusions.

Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Jan 8.

[Epub ahead of print], PMID: 24401022.

4. True. An additional 5% to 10% of

patients with ET and PMF also have activating mutations in the MPL gene.

Klampfl T, Gisslinger H, Harutyunyan AS, et al.

Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:23792390, PMID: 24325356.

Nangalia J, Massie CE, Baxter EJ, et al. Somatic

in NEJM M emphasized that palliative care is suffering from an identity crisis that is limiting its utility to only those enrolled in hospice or admitted to the hospital.

9. True or False. A Phase II study

of alisertib (Millennium), an aurora A kinase inhibitor, published in the Journal of Clinical Oncology showed reassuring activity of this agent in patients with relapsed and refractory aggressive nonHodgkin lymphomas.

10. True or False. A recent study

reported that a peripheral blood absolute lymphocyte count (ALC) and absolute monocyte count (AMC) ratio of 2 or higher at diagnosis remained an independent prognostic factor for OS, PFS and time to progression after adjusting for International Prognostic Index (IPI) score in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

ASH 2013 Oral Abstracts: Highlights—Part II

11.

True or False. PMF: In a Phase III, randomized, placebo-controlled, three-arm study of 289 MF patients with myelofibrosis treated with

CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391-2405, PMID: 24325359.

5. False. Among patients with ET or

PMF without JAK2 or MPL mutation (nonmutated), CALR mutations in exon 9 were detected in 67% of those with ET and 88% of those with PMF. In ET and PMF, CALR exon 9 mutations and JAK2 and MPL mutations were mutually exclusive. Resequencing in 1,107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. Incorporation of these remarkable observations will aid in the approach to patients suspected of having a diagnosis of either ET or PMF. Klampfl T, Gisslinger H, Harutyunyan AS, et al.

Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:23792390, PMID: 24325356.

6. True. Patients with a CALR exon

9 mutation had a lower cumulative incidence of thrombosis than those with the JAK2 V617F mutation: The cumulative incidence at 10 years was 11% (95% confidence interval [CI], 6.3%-17.1%) in the

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

fedratinib (Sanofi) 400 or 500 mg once daily demonstrated clinically meaningful and statistically significant reductions in splenic volume and MF-associated symptom burden versus placebo.

12.

True or False. PMF: Imetelstat (Geron) demonstrated morphologic and molecular remissions in PMF.

13. True or False. Myelodysplastic

syndrome (MDS): In a Phase II study, the combination of azacitidine (AZA) and vorinostat (Zolinza, Merck) was superior to AZA alone in patients with MDS.

14. True or False. MDS: Thera-

py with AZA in patients with trisomy 8 or del(5q) abnormalities was associated with a significantly higher complete response (CR) rate when compared with patients harboring other cytogenetic abnormalities in MDS.

former group versus 21% (95% CI, 16.6%25.7%) in the latter group ((P=0.003). The median OS at 10 years was 91.1% in ET and 11 years in PMF without CALR exon 9 mutation compared with 96.9% in ET and 21.4 years in PMF with CALR exon 9 mutation.

Klampfl T, Gisslinger H, Harutyunyan AS, et al.

Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:23792390, PMID: 24325356.

7. E. Refractory anemia with RARS-

T is a provisional entity in the current World Health Organization classification (2008) and is thought to be a myelodysplastic/myeloproliferative neoplasm. SF3B1 (splicing factor 3b, subunit 1) mutations were the most frequently observed in patients with this entity. A recent report published in Haematologica suggested screening for JAK2 V617F and SF3B1 mutations in all confirmed or suspected RARS-T patients to facilitate diagnosis and distinguish RARS-T from other disease entities or reactive conditions.

Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2014 • CLINICALONCOLOGY.COM

by the

numbers

100

Baseline symptoms and discontinuation

Patient Symptoms Before AI Therapy Predict Adherence

AI, aromatase inhibitor; OR, odds ratio

Discontinued AI Continued AI

OR 1.91 P=0.002 OR 1.66 P=0.015

Patients, %

Noncompliance with aromatase inhibitor (AI) therapy within the first year is associated with patientreported symptoms before initiation of AI therapy, particularly poor sleep quality. This finding comes from a study of 503 patients being treated with AIs, presented at the recent San Antonio Breast Cancer Symposium (S3-02). According to the researchers, up-front management of these symptoms and treating the constellation of symptoms, rather than focusing on individual symptoms, may improve compliance with AI therapy.

OR 1.76 P<0.001

80

60

40

20

0 Depression

Anxiety

Courtesy of Norah Henry, MD.

Poor sleep

Feeling tired

Forgetfulness

Difficulty concentrating

Joint pain

Vaginal dryness

Symptoms before AI initiation

myeloproliferative neoplasms. N Engl J Med. 2013;369:2379-2390, PMID: 24325356.

Jeromin S, Haferlach T, Grossmann V, et al.

High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms. Haematologica.

2013;98:e15-e17, PMID: 22929973.

8. True. To ensure that patients

receive the best care throughout their disease trajectory, experts believe that palliative care should be initiated alongside standard medical care for patients with serious illnesses. Palliative care is not synonymous with hospice care.

According to a field-tested definition developed by the Center to Advance Palliative Care and the American Cancer Society, “Palliative care is appropriate at any age and at any stage in a serious illness, and can be provided together with curative treatment.”

Parikh RB, Kirch RA, Smith TJ, Temel JS. Early specialty palliative care—translating data in oncology into practice. N Engl J Med. 2013;369:23472351, PMID: 24328469.

9. True. Forty-eight patients with

relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), transformed follicular lymphoma, Burkitt’s lymphoma or non-cutaneous T-cell lymphoma were enrolled in this study. The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of

one with Burkitt’s lymphoma, two of five with transformed follicular lymphoma, and four of eight with non-cutaneous T-cell lymphoma. On the basis of these findings, further studies are under way.

of fedratinib on hold after myelofibrosis patients in the studies began to develop Wernicke’s encephalopathy. This adverse event has not been reported with other JAK2 inhibitors.

Friedberg JW, Mahadevan D, Cebula E, et al.

Phase II study of alisertib, a selective aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas. J Clin Oncol. 2014;32:44-50, PMID: 24043741.

Pardanani A, Harrison CN, Cortes JE, et al.

Results of a randomized, double-blind, placebo-controlled Phase III study (JAKARTA) of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis (MF). ASH Annual Meeting Abstracts. Blood. 2013;122:393.

10. True. One hundred and three

consecutive patients with NLPHL who were followed at Mayo Clinic from 1974 to 2010 were included in the study. After adjusting for the IPI, ALC/AMC at diagnosis remained an independent prognostic factor for OS (hazard ratio [HR], 0.33; 95% CI, 0.15-0.71; P<0.004); lymphoma-specific survival (HR, 0.05; 95% CI, 0.01-0.68; P<0.002); PFS (HR, 0.30; 95% CI, 0.14-0.60; P<0.006) and time to progression (HR, 0.06; 95% CI, 0.040.30; P<0.004). ALC/AMC-DX is a lowcost, already standardized, biomarker to predict clinical outcomes in NLPHL. If validated, this blood test could potentially be used as a simple biomarker for risk stratification in NLPHL. Porrata LF, Ristow K, Habermann TM, et al.

Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in nodular lymphocyte-predominant Hodgkin lymphoma. Br J Haematol.

2012;157:321-330, PMID: 22360654.

Advani RH, Hoppe RT. How I treat nodular lymphocyte predominant Hodgkin lymphoma.

Blood. 2013;122:4182-4188, PMID: 24215035.

12. True. In this investigator-spon-

sored single-center study, imetelstat, an inhibitor of human telomerase, was administered to patients with high- or intermediate 2-risk PMF. The overall response rate was 44%. This included five (28%) patients who met the bone marrow and peripheral blood morphologic criteria for CR (n=4) or partial response (n=1) and three patients with clinical improvement, pending validation of response duration and resolution of drug-induced grade 1 thrombocytopenia. The four (22%) patients achieving CR experienced reversal of bone marrow fibrosis and recovery of normal megakaryocyte morphology. The observed morphologic and molecular remissions confirm selective anticlonal activity.

Tefferi A, Begna K, Laborde RR, et al. Imetelstat, a telomerase inhibitor, induces morphologic and molecular remissions in myelofibrosis and reversal of bone marrow fibrosis. ASH Annual Meeting Abstracts. Blood. 2013;122:662.

11. True. Nonetheless, FDA ordered 13. True.

Sanofi to put its ongoing clinical trials

Subcutaneous AZA 75 mg/m2 once a day for seven days in

combination with oral vorinostat 300 mg twice a day from days 3 to 9 resulted in median OS and duration of response of 37.4 and 23 months, respectively. An intergroup study (SWOG-S1117) comparing AZA and vorinostat with either AZA alone or combined with lenalidomide (Revlimid, Celgene) is under way.

Silverman LR, Verma A, Odchimar-Reissig R, et al. A Phase II trial of epigenetic modulators vorinostat in combination with azacitidine (azaC) in patients with the myelodysplastic syndrome (MDS): initial results of study 6898 of the New York Cancer Consortium. ASH Annual Meeting Abstracts. Blood. 2013;122:386.

14.

True. In this retrospective analysis of 878 patients, baseline cytogenetic pattern generally did not predict response to AZA therapy with the exception of patients harboring trisomy 8 (21%) or del(5q) (18.5%). Also, patients harboring 3q26 abnormalities had inferior response rates. None of the other cytogenetic-specific abnormalities or groups and none of the Revised International Prognostic Scoring System cytogenetic categories had any significant effect on CR to AZA. Sebert M, Komrokji RS, Sekeres MA, et al.

Impact of cytogenetics and cytogenetic response on outcome in myelodysplastic syndromes (MDS) treated with azacitidine (AZA): a collaborative study in 878 patients. ASH Annual Meeting Abstracts. Blood. 2013;122:389.

Muhammad Zaidi, MD, assisted in preparing the manuscript.

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