PMOSept13

A Peer-Reviewed Journal

September 2013 Volume 2 • Number 6

BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

PM O

The official publication of

Global biomarkers Consortium Clinical Approaches

TM

to Targeted Technologies

TM

Personalized Medicine in Oncology TM

IMMUNOTHERAPY How Do Melanoma Experts Use the New Agents?……………………............................Page 306

INTERVIEW WITH THE INNOVATORS Utilizing a Personalized Diagnostic in a Class of Hodgkin Lymphoma Patients: An Interview With Lawrence M. Weiss, MD, of Clarient Diagnostic Services, Inc...............................Page 308

HEMATOLOGIC MALIGNANCIES CME Advances in the Treatment of Hematologic Malignancies: Updates from ASCO, EHA, and ICML 2013 ..................................................Page 318

RENAL CELL CARCINOMA Genetic Susceptibility to Renal Cell Carcinoma …………………….......................Page 338

OVARIAN CANCER Olaparib Maintenance Therapy Slows Progression in Patients With Ovarian Cancer and BRCA Mutations….................................Page 343

THE LAST WORD To PARP or Not to PARP – What Is the Question? ….................................................Page 349

www.PersonalizedMedOnc.com © 2013 Green Hill Healthcare Communications, LLC

In partnership with

Important Safety Information WARNINGS AND PRECAUTIONS: • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%),

thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (N=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (N=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).

Infections were the most common type of serious adverse event reported in both Study 1 (N=102) and Study 2 (N=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.

The most common adverse reactions regardless of causality in Study 1 (N=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (N=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

ISTODAX® is a registered trademark of Celgene Corporation. ©2012 Celgene Corporation 09/12 US-IST120024

INDICATIONS THE FIRST AND ONLY • Treatment of peripheral T-cell lymphoma (PTCL) in patients DRUG APPROVED IN BOTH who have received at least one prior therapy PTCL AND CTCL • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

www.istodax.com Please see Important Safety Information on adjacent page.

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

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Only

ISTODAX® (romidepsin) for injection For intravenous infusion only

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)

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The following is a brief summary only; see full prescribing information for complete product information.

1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle.

Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.

Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients

with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

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Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin® (a registered trademark of BristolMyers Squibb Pharma Company) or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors.

Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort.

7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus.

Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were Cosmos Communications

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Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).

Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.

Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

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seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area

noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)].

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)] 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of romidepsin on the heart-rate corrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8, 10 or 12 mg/m2 as a 1–hour infusion. Patients received premedications with antiemetics. No large changes in the mean QTc interval (> 20 milliseconds) from baseline based on Fridericia correction method were detected in the trial. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded because of the limitations in the trial design.

Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6 hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin.

Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively).

These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2012 Celgene Corporation. All Rights Reserved.

U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBAXPI.004/PPI.004 03/12

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was Cosmos Communications

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17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients.

Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)].

• Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)].

• Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2].

• Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)].

• Use in Pregnancy If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling.

[See Warnings and Precautions (5.5)].

• Patients should be instructed to read the patient insert carefully.

SEPTEMBER 2013

VOLUME 2, NUMBER 6 PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko phil@greenhillhc.com Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Publisher Russell Hennessy russell@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Strategic Editor Robert E. Henry

TABLE OF CONTENTS

Senior Copy Editor BJ Hansen

IMMUNOTHERAPY

306

Copy Editor Rosemary Hansen

How Do Melanoma Experts Use the New Agents?

Production Manager Marie RS Borrelli

Caroline Helwick The author presents a summary from expert talks at the World Cutaneous Malignancies Congress on the treatment landscape in metastatic melanoma.

The Lynx Group President/CEO Brian Tyburski

INTERVIEW WITH THE INNOVATORS

308

Chief Operating Officer Pam Rattananont Ferris

Utilizing a Personalized Diagnostic in a Class of Hodgkin Lymphoma Patients: An Interview With Lawrence M. Weiss, MD, of Clarient Diagnostic Services, Inc.

Vice President of Finance Andrea Kelly

PMO talks with Dr Lawrence Weiss, Medical Director of Clarient Diagnostic, about personalized medicine, the implications of costs to a burdened healthcare system, and the venues in which MultiOmyx is best used.

Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

HEMATOLOGIC MALIGNANCIES CME

318

Advances in the Treatment of Hematologic Malignancies: Updates from ASCO, EHA, and ICML 2013 Jennifer Brown, MD, PhD; Stephanie A. Gregory, MD; Ruben A. Mesa, MD, FACP; David P. Steensma, MD, FACPBU

Quality Control Assistant Theresa Salemo Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

CONFERENCE NEWS

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346

Creative & Design Assistant Lora LaRocca

Genomic Sequencing Assay Potentially a Game Changer Pathways Creating More and More Value Ponatinib Given Early May Stem Resistance in CML Bevacizumab Maintenance Improves Survival in mCRC, but Added Erlotinib Is of No Value Genomic Sequencing Uncovers the Genetic Landscape of Primary CNS Lymphoma

Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma

OUR MISSION The mission of Personalized Medicine in Oncology is to deliver practice-changing information to clinicians about customizing healthcare based on molecular profiling technologies, each patient’s unique genetic blueprint, and their specific, individual psychosocial profile, preferences, and circumstances relevant to the process of care.

OUR VISION Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

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Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 fax: 732-656-7938

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he Global Biomarkers Consortium™ (GBC) is a community of worldrenowned healthcare professionals who will convene in multiple educational forums in order to better understand the clinical application of predictive molecular biomarkers and advanced personalized care for patients.

TABLE OF CONTENTS

Global biomarkers Consortium Clinical Approaches

(Continued)

TM

RENAL CELL CARCINOMA

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Genetic Susceptibility to Renal Cell Carcinoma

Cristi Radford, MS, CGC The author provides a summary of the most well-recognized syndromes associated with RCC and provides recommendations for genetic counseling and testing.

OVARIAN CANCER

343 Olaparib Maintenance Therapy Slows Progression in Patients With Ovarian Cancer and BRCA Mutations

Alice Goodman

to Targeted Technologies

TM

Save the date for the Second Annual Conference, October 4-6, 2013 Visit www.globalbiomarkersconsortium. com to register

The author provides a summary of data from ASCO on the clinical benefit of olaparib in patients with ovarian cancer and a BRCA mutation.

THE LAST WORD

349 To PARP or Not to PARP – What Is the Question?

Robert Emmett Henry

Mr Henry discusses the emerging role of PARP inhibitors in fighting cancer.

Professional Experience of GBC Attendees 26.7%

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 6 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copy­right ©2013 by Green Hill Health­care Com­muni­cations, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should be ad­dressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPART­MENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

1-3 years 3-5 years 5-10 years 10-20 years >20 years

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GE Healthcare Clarient Diagnostic Services

Things aren’t always what they seem. Get the complete picture.

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Introducing a Clarient validated lab-developed test using MultiOmyx to assess 9 antibodies on a single slide at a single cell – maximizing the molecular data from precious patient samples

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Leverages imaging data technology to visualize disease and the relationship between different biomarkers and the tumor environment

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Helps pathologists diagnose previously undiagnosable lymphoma cases and may help prevent rebiopsy for additional diagnostic material

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GE, the GE Monogram, and imagination at work are trademarks of General Electric Company.

GE Healthcare, a division of General Electric Company.

Clarient Diagnostic Services, Inc. is a division of General Electric Company.

MultiOmyx is a trademark of General Electric Company.

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EDITORIAL BOARD

EDITORS-IN-CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania Al B. Benson III, MD Northwestern University Chicago, Illinois SECTION EDITORS Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee

Lyudmila Bazhenova, MD University of California, San Diego San Diego, California

Afsaneh Motamed-Khorasani, PhD Radient Pharmaceuticals Tustin, California

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts

Kenneth Bloom, MD Clarient Inc. Aliso Viejo, California

Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California

Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts

David A. Proia, PhD Synta Pharmaceuticals Lexington, Massachusetts

Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil

Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain

Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Stephen Gately, MD TGen Drug Development (TD2) Scottsdale, Arizona

Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts

Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio

K. Peter Hirth, PhD Plexxikon, Inc. Berkeley, California

Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana EDITORIAL BOARD Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

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Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan Howard L. Kaufman, MD Rush University Chicago, Illinois Katie Kelley, MD UCSF School of Medicine San Francisco, California Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington Gene Morse, PharmD University at Buffalo Buffalo, New York

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Hope S. Rugo, MD University of California, San Francisco San Francisco, California Danielle Scelfo, MHSA Genomic Health Redwood City, California Lee Schwartzberg, MD The West Clinic Memphis, Tennessee John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida Darren Sigal, MD Scripps Clinic Medical Group San Diego, California David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

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Think outside the box to see inside the cell.

Are your breast cancer assays missing the real story?

The conventional thinking in breast cancer diagnosis relies on the identification of ER, PR and HER2 receptors. To us, that misses the biggest part of the picture. That’s why our scientists created a new approach to let you see inside the cell and learn if the molecular pathway is functional or not. By understanding which compromised pathway is fueling the tumor growth, you can target therapies specifically to your patient’s molecular profile to improve outcomes.

The SYMPHONY™ Personalized Breast Cancer Genomic Profile is the only test platform that can give you this comprehensive insight. Now you can safely eliminate indeterminate results and have confidence that your treatment decisions are targeting the correct molecular pathway.

Breast Cancer Recurrence Signature Molecular Subtyping Signature

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Call us at 888.321.2732 customercare@agendia.com | www.agendia.com ©Copyright 2013 Agendia. All rights reserved. Agendia, MammaPrint, BluePrint, TargetPrint and TheraPrint are registered trademarks of Agendia. SYMPHONY is a trademark of Agendia.

LETTER TO OUR READERS

Illustrating the New Era of Personalized Medicine Dear Colleague,

I

t gives us great pleasure to present this issue of Personalized Medicine in Oncology (PMO). Over the past several months, we have thoroughly examined every aspect of the journal – appearance, readability, and most importantly, editorial content.

You will see the result of our efforts in the following ways: Al Benson, MD

• Immunotherapy The immune system is back in the discussion of how to fight cancer. Many exciting new agents are being studied in clinical trials in diseases such as non–small cell lung cancer, melanoma, and kidney cancer, to name just a few. PMO will keep readers up to date on advances in this area and discuss what it means for patients.

• Interview With the Innovators The world of personalized medicine is a rapidly changing, ever-evolving state involving many stakeholders on the front lines of its creation: physicians, industry, researchers, patient advocates, and payers. PMO seeks out the leaders in these sectors and brings you their game-changing strategies, missions, and impact on personalized oncology care.

• The Last Word In this department, our Strategic Editor and Editor in Chief sum up thoughts on various overriding themes in the world of personalized medicine.

• Journal Design You will notice a redesign in the look of the entire journal. This new, streamlined design is intended to make the journal easier to read and navigate.

We believe these will greatly enhance your reading experience. Please let us know what you think!

E-mail our Editorial Director, Kristin Siyahian at ksiyahian@the-lynx-group.com. We look forward to and welcome your feedback.

Sincerely,

Al Benson, MD Editor in Chief Personalized Medicine in Oncology

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Together,

we are moving medicine forward Get to know Life Technologies, your partner in advancing individualized medicine Building on our legacy of developing high-quality laboratory instruments and systems, we proudly offer you our most innovative technologies and diagnostics to enable the next generation in care.

See for yourself at lifetechnologies.com/clinical Š2013 Life Technologies Corporation. All rights reserved. The trademarks mentioned herein are the property of Life Technologies Corporation and/or its affiliate(s) or their respective owners. CO28208 0813

IMMUNOTHERAPY

How Do Melanoma Experts Use the New Agents?

Caroline Helwick

M

elanoma experts gathered at the second annual World Cutaneous Malignancies Congress to debate the optimal means of treating melanoma using the new agents and to share predictions about the future treatment landscape in metastatic melanoma.

Their insights are shared in this report.

Metastatic Melanoma: Which Drug First?

Despite excitement over the robust responses observed with the BRAF inhibitors, the lack of durability of response (ie, the development of resistance) has dampened enthusiasm for them, according to speakers at this meeting. For this reason, immunotherapy is becoming the clinicians’ first choice for initiating treatment in many cases, but treatment should always be personalized, they said.

Immunotherapy is becoming the clinicians’ first choice for initiating treatment in many cases, but treatment should always be personalized.

Mario Sznol, MD, professor of medicine at Yale University School of Medicine, indicated that he often starts patients on the anti–CTLA-4 antibody ipilimumab, to which patients slowly build an immune response over 3 to 6 months but, once responding, often maintain this response long-term. The overall survival rate is approximately 50% after treatment with ipilimumab.

“With ipilimumab you get durable remissions, but you need time to get there. For patients progressing or declining rapidly, and for those with poor performance status, it’s not the drug to use first,” he said.

These patients, if they have BRAF-mutated tumors, will typically receive a BRAF inhibitor, but even in this case, “we have taken the strategy that once we get them to their best response, we stop the targeted therapy and start ipilimumab,” he added.

Antoni Ribas, MD, PhD, professor of medicine, surgery, and molecular and medical pharmacology at the University of California, Los Angeles, took a more flexible position. “I agree that the majority of patients pro­ gress on BRAF inhibitors, but not all. If a patient comes

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in even with a small-volume indolent tumor, I may start with a BRAF inhibitor because the patient may want quick response for personal reasons. If we only use BRAF inhibitors in the worst cases and assume we are only getting temporary benefit, then we are failing to get the full spectrum of benefit of these drugs,” he offered.

Steven O’Day, MD, director of the Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center, emphasized that with so much speculation, long-term follow-up is greatly needed. “The follow-up on the BRAF inhibitors is much shorter than for immunotherapy, where the data are more mature. But at the same time, there is a tremendous impression that immunotherapy only works in small-volume, indolent disease. What really matters is the kinetics of response to ipilimumab: if the patient has 2 to 3 months to live, he or she cannot possibly benefit from a drug that takes 3 to 6 months to work.”

While an ASCO 2013 study showed that the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to ipilimumab improved overall survival and reduced toxicity, the panelists were not ready to act on these findings. “I am not quite ready to give GM-CSF. It’s expensive, and it’s a tedious injection process. Although this is a strong signal we need to follow up on, I would like to see more data,” O’Day commented.

Combination Therapy Sznol said he is increasingly using a BRAF inhibitor combined with a MEK inhibitor (trametinib), which greatly reduces the toxicity of vemurafenib and da­ brafenib. “With vemurafenib alone, lots of patients feel bad. I would much rather give both drugs. We have been doing that successfully, just based on toxicity issues and the reduced risk of secondary skin cancers,” he said.

O’Day agreed on the value of combining the 2 targeted agents. “The last thing you want is for your patient to progress on monotherapy. You can’t predict that,” he said.

Jeffrey Sossman, MD, professor of medicine and director of the Melanoma and Tumor Immunotherapy Program at Vanderbilt-Ingram Cancer Center, weighed in.

“Right now, there is no indication for combination therapy. The combination does have some efficacy with regard to side effects, but there is just a few months’ benefit in PFS [progression-free survival], not an overall survival benefit,” he said.

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He added that for the patient progressing after a long response on a BRAF inhibitor, the addition of a MEK inhibitor could be advantageous.

Sossman further pointed out that while the combination of a BRAF and MEK inhibitor can reduce the side effects associated with vemurafenib, the combination of trametinib plus dabrafenib can actually increase fever and chills versus dabrafenib alone.

“Dabrafenib does not cause the photosensitivity we see with vemurafenib, and this is important, but it does cause fever and chills, and if you add trametinib these go up dramatically. About 60% to 70% of patients have significant fever and chills [with the combination],” he said. He predicted that while the combination may become the standard, “it is not clear that all patients or even any patient should get this up front.”

According to Ribas, one advantage of the combination is durability of response. “There is no doubt that with the combination there are patients with durable responses. The question is whether the targeted therapies can be discontinued and have patients remain in remission,” he said. “That may be the difference between this approach and immunotherapy. With immune treatment, I think we can discontinue the drugs. I would like to see a trial in which patients are taken off these drugs and have complete responses maintained. That would be important information.”

The Anti–PD-1/PD-L1 Drugs Will Change the Landscape The speakers agreed that the landscape is about to change, thanks to antibody-mediated blockade of the programmed death 1 protein (PD-1) and its ligand (PDL1). The anti–PD-1/PD-L1 monoclonal antibodies elicited excitement at the 2013 ASCO Annual Meeting, and speakers at this meeting said clinical trials of these compounds were a high priority.

In phase 1 studies reported at ASCO, nivolumab

paired with ipilimumab produced responses in 40% of heavily pretreated patients and led to durable responses in the vast majority, while responses to MPDL3280A were observed in 21% of refractory patients (36% of those staining positive for PD-1).

The possibility of using anti–PD­-1/PD-L1 monoclonal antibodies in combination with other melanoma drugs holds great promise.

The possibility of using these agents in combination with other melanoma drugs holds great promise, according to the specialists, though the trade-off may be an increase in toxicity. “With the combination of nivolu­ mab and ipilimumab, without question we have seen a higher incidence of toxicity, but it was qualitatively similar to ipilimumab alone,” said Sznol, who led the phase 1 trial of nivolumab presented at ASCO 2013. “I think if the combination is a better regimen, then the toxicity is worth it to obtain a better outcome.”

He emphasized that randomized trials must be done to evaluate such combinations. “I still don’t know if nivolumab/ipilimumab is better than nivolumab alone, or better than lambrolizumab alone,” Sznol continued.

“However, the impression is that with large-bulk, rapidly progressive disease, with the combination we are seeing responses within a period of weeks.”

Ribas commented, “The data on nivolumab/ipilimumab are so impressive, it’s hard to believe either drug alone is as good. But I agree that we must be careful about comparing small studies.”

Sznol further noted that one particular anti–PD-1/ PD-L1 agent has not been shown to be superior to another, and that the study populations have not been completely comparable. “At the end of the day,” he said, “we always need randomized trials.” u

GBC_2013Conf_horizontalV291312_Layout 1 9/13/12 12:22 PM Page 1

SECOND ANNUAL CONFERENCE

GLOBAL BIOMARKERS CONSORTIUM

™

Clinical Approaches to Targeted Technologies

™

October 4-6, 2013 • The Seaport Boston Hotel • 1 Seaport Lane • Boston, MA 02210

REGISTER TODAY AT www.globalbiomarkersconsortium.com

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INTERVIEW WITH THE INNOVATORS

Utilizing a Personalized Diagnostic in a Class of Hodgkin Lymphoma Patients:

An Interview With Lawrence M. Weiss, MD, of Clarient Diagnostic Services, Inc.

C

larient Diagnostic Services, Inc, a GE Healthcare Company, combines innovative diagnostic technologies with pathology expertise to assess and characterize cancer. Their stated mission is to “become the leader in cancer diagnostics by dedicating ourselves to collaborative relationships with the healthcare community to translate cancer disLawrence M. covery and research into better patient care.”

Weiss, MD The rise of individualized medicine as the new direction in oncology has created the need for innovative diagnostic technologies. Clarient is meeting this need by commercializing new lab-developed tests and companion diagnostic markers for therapeutics in breast, prostate, lung, and colon cancers and leukemia/lymphoma. Most recently, they have introduced the Hodgkin

Lymphoma Profile by MultiOmyx™, an aid to a pathologist’s diagnosis of CD30-positive lymphoma cases with difficult morphology or otherwise insufficient tissue to adequately evaluate the case. This test utilizes a new pathology platform that uses proprietary methodology to assess multiple proteins from a single tissue section at a single-cell level. If you have a small amount of tissue, you do not have to sacrifice or choose between important markers. You can assess them all.

We had the pleasure of meeting with Dr Lawrence Weiss in his Aliso Viejo, California, office to talk about his definition of personalized medicine, the implications of costs to a burdened healthcare system, and the venues in which MultiOmyx is best used. To view the interview in its entirety, please go to www.PersonalizedMedOnc. com/videolibrary.

PMO Thank you so much for speaking with us, Dr Weiss. As a hematopathologist, how do you define personalized medicine in oncology?

Dr Weiss Personalized medicine is different things to different people. As a hematopathologist, I think it’s matching the person’s cancer to the best diagnosis and the best treatment modalities.

PMO Personalized medicine remains sporadic and occurs mainly at well-funded academic medical centers or prompted by physicians who really understand the genetic principles behind molecular biomarkers and how

to assess them appropriately. How can this situation change so that personalized medicine in oncology can be made available broadly to patients managed by the community caregivers?

Dr Weiss Clarient’s objective has always been to deliver reliable information to the community cancer caregivers, to help keep cancer care local. Bringing personalized medicine to the community and individual patients is a difficult issues – the biggest driver is cost. We’re talking about expensive diagnostic and treatment procedures. We not only have to provide innovative diagnosis and treatment, but we have to do it at a cost that is affordable to our healthcare system. Juggling the two is a difficult proposition.

PMO What are the barriers and opportunities for this to actually occur, bringing these types of molecular biomarkers and genetic principles into the community?

Dr Weiss The basic barrier is cost. The medical profession needs to convince the payers – government and private payers – that the diagnostic modalities and the treatment modalities that we want to bring to individual patients will have benefit to those patients. But just by virtue of it being individualized therapy, it may be hard to prove in clinical studies, at least in clinical studies as

Lawrence M. Weiss, MD, is Medical Director of Clarient Diagnostic Services. He is Chairman Emeritus of the Department of Pathology at the City of Hope National Medical Center. He received his BS summa cum laude and his MD summa cum laude from the University of Maryland. He completed a residency in anatomic pathology at the Brigham & Women’s Hospital in Boston and a fellowship in surgical pathology at Stanford University Medical Center. He was previously an Assistant Professor at Stanford and Director of Surgical Pathology at the City of Hope.

Dr Weiss’ interests lie in surgical pathology, hematopathology, and immunohistochemistry.

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we provide them today. As a result, we have to invest in resources to prove to payers that our innovative therapies and treatments are going to be effective, and try to do it at a reasonable cost so that when it translates to reimbursable procedures and treatments, it’s still within the bounds of the healthcare budget.

PMO The Hodgkin Lymphoma Profile by MultiOmyx is being launched as a Clarient-validated lab-developed test which uses a new proprietary methodology to aid pathologists and oncologists in delivering a genomic profile they can use as a guide in the treatment of difficult lymphoma cases. Please explain the differentiating factors of this test as opposed to other laboratory-developed tests.

Dr Weiss When we speak of personalized medicine, we usually talk about the therapy side being personalized. But in this particular case, MultiOmyx is a personalized diagnostic. It will be utilized in lymphoma – but not every case. It will be utilized in certain types of biopsies showing particular findings as a way of making a more precise and accurate diagnosis of Hodgkin lymphoma so people can get the correct therapies that they deserve.

PMO Issues raised regarding genomic profiling include the accuracy, sensitivity, and reproducibility of results. If the right drug is to be delivered to the right patient at the right time, we have to have confidence in the results of molecular biomarker analyses. Can you please compare MultiOmyx’s tests versus genomic tests and also as opposed to proteomic tests?

Dr Weiss As of this time, genomic tests are really not helpful in the accurate diagnosis of Hodgkin lymphoma.

Currently, Hodgkin lymphoma is diagnosed by having a pathologist look down a microscope, supplemented by protein studies – immunohistochemical analyses – performed in sections taken from paraffin-embedded blocks.

MultiOmyx offers a superior way of looking at multiple antigens in tissue.

First, in immunohistochemistry it’s 1 antibody, 1 section; with MultiOmyx you can get numerous proteins looked at in 1 section. Therefore, if you have small biopsies, you will never run out of tissue. In fact, you’ll preserve the tissue that’s there for additional studies if they’re needed, whereas with immunohistochemistry you’re very limited.

Second, immunohistochemistry has the limitation that proteins are being examined on different tissue sections; you never quite look at the same cell. Hodg­ kin lymphoma has a unique morphologic appearance in which the neoplastic element is only about 1% of the infiltrate that you see. So when you look at antibody studies you’ll see, for example, some CD30-positive cells, you’ll see some CD15-positive cells. Both are

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Multiplexed fluorescence microscopy and image acquisition (MultiOmyxTM) was performed using the 9 stains in the Hodgkin Lymphoma Profile. The hallmark Reed-Sternberg cell (center of image) shows expression patterns of both CD30 and CD45. The antigen illustrated can be changed by moving the vertical divider left or right. characteristics of Hodgkin lymphoma, and when you see them on the same cell it helps you toward that diagnosis.

But when you look on the typical immunohistochemistry studies, you’re never quite sure whether it’s the same cell expressing both antigens or it’s 2 separate cell populations that express those antigens.

With MultiOmyx, you can look at your CD30 or other antigen stain and see how those positive cells are stained with other markers so you have a direct comparison, whereas with immunohistochemistry there’s a little bit of guesswork in indirect comparison.

PMO Incorporating a molecular biomarker profile in the management plan for all cancer patients is an extremely expensive undertaking. How should patients be selected for biomarker analysis?

Dr Weiss There are 2 ways to select patients for biomarker analysis. First, there has to be effective therapy. If there’s no effective therapy, you can do all the analysis that you want, and it really won’t help the individual patient. There has to be something on the treatment end that one could be offered. It could be 1% of patients, it could be 70% of patients, it could be 0.1% of patients,

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Here the very same Reed-Sternberg cell as pictured on the previous page is evaluated for expression patterns of CD15 and CD79a. The antigen illustrated can be changed by moving the vertical divider left or right. but there has to be some benefit should a certain profile be obtained.

But I look at it another way as well. I look at it from the standpoint of whether there is something in the patient’s cancer that will benefit in diagnosis as well from a particular modality.

Hodgkin lymphoma is generally a difficult diagnosis.

First of all, it’s not a very common lymphoma, and many pathologists have limited experience with the diagnosis, so that makes it hard right from the start.

Hodgkin lymphoma is generally a difficult diagnosis....MultiOmyx can help you by more frequently obtaining diagnoses on small pieces of tissue.

Second, quite often the differential diagnosis of Hodg­kin versus something else, even benign conditions, can be quite difficult even for a very experienced hemato­pathologist. So if you have a treatment modality for those small subsets of hard cases, I think that’s personalized medicine as well.

PMO Should the Hodgkin Lymphoma Profile by

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MultiOmyx be added to the management plan for all patients with Hodgkin lymphoma and, if so, how can the added cost be justified?

Dr Weiss At this point in time I don’t think that MultiOmyx should be included in the diagnostic regimen for all patients with Hodgkin lymphoma. I think it should be included when the pathologist thinks there is a chance it may help the diagnosis.

So where may it help? Currently excisional biopsies represent the most common diagnostic medium because Hodgkin or any lymphoma diagnosis is a difficult one, and an important one, and you do not want to skimp on tissue. But sometimes you have to do needle biopsies; for example, a biopsy of a large mediastinal mass. Cracking the chest would be an awful lot of money as well as morbidity for the patient. If MultiOmyx can help you by more frequently obtaining diagnoses on small pieces of tissue, this actually is going to be very cost-effective.

I had a case the other day where the diagnosis in the referring pathologist’s mind, and in my mind as well, was Hodgkin versus non-Hodgkin lymphoma. We threw this on MultiOmyx and were able to get a definitive diagnosis. That’s going to save a lot of money for the system by preventing a second excisional biopsy.

Where will MultiOmyx be in the future? I think we may go away from more excisional biopsies for possible patients with lymphoma and go more to core needle biopsies to make the diagnosis, and I think MultiOmyx is going to help with that. It may be more expensive than routine immunohistochemistry, but when you factor in the cost of an excisional biopsy versus the cost of an easy outpatient needle biopsy, you may find that going the latter route is going to be the more cost-effective, and from a quality standpoint, the better way.

PMO How will MultiOmyx help cancer patients who either do not respond to therapy or acquire resistance to standard therapy?

Dr Weiss Currently for Hodgkin lymphoma, patients with favorable low-stage disease have about a 90% cure rate. For those with a higher stage or more unfavorable features, the cure rate is still relatively high, but on the order of 75% to 80%.

Typically at some point during the treatment of a patient with Hodgkin lymphoma, some radiologic studies are performed, perhaps a PET-CT scan to see if the patient is responding. In a small percentage of the cases, the patient may not respond to therapy. Is it because the patient had the correct diagnosis of Hodgkin lymphoma and is just not responding to therapy, or is there a possibility that it was an incorrect diagnosis?

Hodgkin is a tough diagnosis. We’ve made a lot of progress in terms of pathology and diagnoses, but I’d still

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SAVE DATE

estimate that perhaps 5% of diagnoses may be incorrect, even by expert hematopathologists who don’t always agree with each other.

So it could be that if a patient is found not to respond, or have an unusual occurrence, that this is a mandate to implement this better technology and either definitively confirm that the original diagnosis is right or that this is 1 of the 5% of cases in which you are treating the wrong disease.

PMO Education of providers, pharmacists, payers, and patients is vital in achieving personalized medicine in oncology. How is GE Healthcare positioning itself in personalizing medicine and oncology as a whole?

Dr Weiss I think GE Healthcare is very interested in personalized medicine and wants to be part of the solution. They want to bring innovative diagnostic modalities that will help guide individualized therapies.

PMO What do you foresee as the future clinical application of personalized medicine when sequencing the entire human genome will hopefully cost less than $1000 within the next several years, and how is GE Healthcare positioned for next-generation sequencing?

Dr Weiss I think there’s an unlimited potential for next-generation sequencing, particularly when the costs do come down to a reasonable point. Clarient recently acquired SeqWright Genomic Services, a DNA sequencing service organization that is well poised to be part of this revolution.

PMO What could be offered to patients without a biomarker that directs a targeted therapy, especially if this impacts a significant percentage of patients?

Dr Weiss I don’t think we ought to be giving individualized treatments without detecting the biomarkers, because we could be overtreating a segment of the population and giving them morbidity, mortality, without any benefits. I’m a big believer that for any personalized medicine therapy there ought to be a corresponding di-

agnostic that will give some probability whether patients will or will not respond to that therapy. I see the two as a yin-yang going together. The diagnostic has to come with the individualized therapy, otherwise it’s not individualized therapy.

PMO Do you foresee a future in which pharmaceutical and biotech companies will not develop new therapeutic agents for oncology if the agent isn’t linked to a biomarker that identifies the patient population most likely to benefit?

Dr Weiss I agree, I don’t see pharmaceutical companies or other biotech companies developing therapies without accompanying biomarkers. I think patients want it, I think payers want it, and it’ll bring cost down, and it’ll prevent morbidity in patients who don’t need that therapy. So I think the two go hand in hand, the diagnostic and the therapeutic.

PMO Thank you so much for your time and insights today.

Dr Weiss My pleasure. u

4TH ANNUAL CONFERENCE

THE

Vol 2, No 6

MAY 7-9, 2014

LOEWS HOLLYWOOD HOTEL, LOS ANGELES, CA l

September 2013

www.PersonalizedMedOnc.com

l

Personalized Medicine in Oncology

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311

INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Iclusig (ponatinib) Unlock efficacy for resistant or intolerant CML and Ph+ ALL patients ™

IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events.

• Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity.

Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig-treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusig-treated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events.

Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient

within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis.

Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

C H R O N I C P H A S E C M L (C P - C M L ) More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved MCyR.

54

%

44%

(144/267)

MCyR 95% CI: 48-60 (118/267)

CCyR 95% CI: 38-50 Most patients who achieved MCyR also achieved CCyR.

Median duration of follow-up was 10 months.1

Efficacy in T315I 70% of CP-CML patients with the T315I mutation (45/64) achieved MCyR (95% CI: 58-81), and 66% (42/64) achieved CCyR (95% CI: 53-77).

Iclusig is a 45 mg oral tablet taken once daily with or without food.

Learn more about Iclusig’s efficacy in patients with the T315I mutation and all phases of resistant or intolerant CML and Ph+ ALL at Iclusig.com.

Tablet is not shown at actual size.

Iclusig was evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once daily. Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR).

Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients.

For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious

tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the brief summary of the Prescribing Information on the following pages, including the Boxed Warning.

Note: Unless otherwise indicated, data presented are from Iclusig [package insert].

Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012.

Reference: 1. Data on file.

Iclusig is a trademark of ARIAD Pharmaceuticals, Inc. ©2013 ARIAD Pharmaceuticals, Inc. All rights reserved.

PB/0513/0019/US

BRIEF SUMMARY Iclusig (ponatinib) Rx only Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

INDICATIONS AND USAGE Iclusig™ (ponatinib) is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

This indication is based upon response rate [see Clinical Studies (14)].

There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Thrombosis and Thromboembolism Arterial Thrombosis Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients.

Serious arterial thrombosis occurred in 8% (34/449) of Iclusigtreated patients. Twenty-one patients required a revascularization procedure (16 patients with coronary revascularization, 4 patients with peripheral arterial revascularization, and 1 patient with cerebrovascular revascularization). Overall, fifty-one patients (11%) experienced an arterial thrombosis event of any grade.

Myocardial infarction or worsening coronary artery disease was the most common arterial thrombosis event and occurred in 21 patients (5%) of Iclusig-treated patients. Eleven of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.

Serious cerebrovascular events were reported in 2% (8/449) of Iclusig-treated patients. Two patients experienced hemorrhagic conversion of the initial ischemic event. Four patients developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery).

Serious peripheral arterial events were reported in 2% (7/449) of Iclusig-treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations.

5.2

1

5.3

5.4

5.5

Thirty of 34 Iclusig-treated patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].

Venous Thromboembolism Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

Hepatotoxicity Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred.

The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts.

The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Congestive Heart Failure Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities.

Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig.

Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

Hypertension Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.

Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations.

Pancreatitis Clinical pancreatitis occurred in 6% (28/449) of patients (5% grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%.

5.6

5.7

5.8

5.9

5.10

Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required.

In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)].

Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].

Fluid Retention Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Cardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients.

The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).

Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Myelosuppression Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ ALL than in patients with chronic phase CML (CP-CML). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

Tumor Lysis Syndrome Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

5.11 Compromised Wound Healing and Gastrointestinal Perforation No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing.

Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing.

5.12 Embryo-Fetal Toxicity Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following adverse reactions are discussed in greater detail in other sections of the prescribing information: • Thrombosis and Thromboembolism [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2) and Dosage and Administration (2.3)] • Congestive Heart Failure [see Warnings and Precautions (5.3)] • Hypertension [see Warnings and Precautions (5.4)] • Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)] • Hemorrhage [see Warnings and Precautions (5.6)] • Fluid Retention [see Warnings and Precautions (5.7)] • Cardiac Arrhythmias [see Warnings and Precautions (5.8)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.9)] The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83%, of the expected 45 mg dose.

Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia.

The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%).

Dose modifications (dose delays or dose reduction) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions (â&#x2030;Ľ5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%).

Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) System Organ Class Any CTCAE Any CTCAE Any CTCAE Any CTCAE Grade Grade Grade Grade Grade Grade Grade Grade (%) 3/4 (%) 3/4 (%) 3/4 (%) 3/4 (%) (%) (%) (%) Cardiac or Vascular disorders Hypertension (a) 68 39 71 36 65 26 53 31 Arterial ischemia (b) 13 7 12 6 8 5 3 0 Cardiac Failure (c) 6 4 6 2 15 11 6 6 Gastrointestinal disorders Abdominal pain (d) 49 10 40 8 34 6 44 6 Constipation 37 2 24 2 26 0 47 3 Nausea 23 1 27 0 32 2 22 0 Diarrhea 16 1 26 0 18 3 13 3 Vomiting 13 2 24 0 23 2 22 0 Oral mucositis (e) 10 1 15 1 23 0 9 3 GI hemorrhage (f) 2 <1 8 1 11 5 9 6 Blood and lymphatic system disorders Febrile neutropenia 1 <1 4 4 11 11 25 25 Infections and infestations Sepsis 1 1 5 5 8 8 22 22 Pneumonia 3 2 11 9 13 11 9 3 Urinary tract infection 7 1 12 1 0 0 9 0 Upper respiratory tract infection 11 1 8 0 11 2 0 0 Nasopharyngitis 9 0 12 0 3 0 3 0 Cellulitis 2 1 4 2 11 3 0 0 Nervous system disorders Headache 39 3 28 0 31 3 25 0 Peripheral neuropathy (g) 13 2 8 0 8 0 6 0 Dizziness 11 0 5 0 5 0 3 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 3 1 11 2 13 0 19 3 Cough 12 0 17 0 18 0 6 0 Dyspnea 11 2 15 2 21 7 6 0 Skin and subcutaneous tissue disorders Rash and related conditions 54 5 48 8 39 5 34 6 Dry skin 39 2 27 1 24 2 25 0 Musculoskeletal and connective tissue disorders Arthralgia 26 2 31 1 19 0 13 0 Myalgia 22 1 20 0 16 0 6 0 Pain in extremity 17 2 17 0 13 0 9 0 Back pain 15 1 11 2 16 2 13 0 Muscle spasms 12 0 5 0 5 0 13 0 Bone pain 12 <1 12 1 11 3 9 3 General disorders and administration site conditions Fatigue or asthenia 39 3 36 6 35 5 31 3 Pyrexia 23 1 31 5 32 3 25 0 Edema, peripheral 13 <1 19 0 13 0 22 0 Pain 8 <1 7 0 16 3 6 3 Chills 7 0 11 0 13 2 9 0 Metabolism and nutrition disorders Decreased appetite 8 <1 12 1 8 0 31 0 Investigations Weight decreased 6 <1 7 0 5 0 13 0 Psychiatric disorders 0 Insomnia 7 0 12 0 8 0 9 Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity.

Treatment-emergent, all causality events (a) derived from blood pressure (BP) measurement recorded monthly while on trial (b) includes cardiac, central nervous system, and peripheral arterial ischemia (c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure (d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort (e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration (f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage (g) includes burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, polyneuropathy

Table 5: Serious Adverse Reactions (SAR) N (%)

Cardiovascular disorders Arterial ischemic event Myocardial infarction or worsening coronary artery disease Stroke or TIA Peripheral arterial disease Hemorrhage CNS hemorrhage Gastrointestinal hemorrhage Cardiac failure Effusions* Atrial fibrillation Venous thromboembolism Hypertension Gastrointestinal disorders Pancreatitis Abdominal pain Blood and lymphatic system disorders Febrile neutropenia Thrombocytopenia Anemia Infections Pneumonia Sepsis General Pyrexia

34 (8%) 21 (5%) 8 (2%) 7 (2%) 22 (4%) 10 (2%) 10 (2%) 20 (4%) 13 (3%) 11 (2%) 10 (2%) 8 (2%) 23 (5%) 17 (4%) 13 (3%) 13 (3%) 12 (2%) 24 (4%) 11 (2%) 14 (3%)

*includes pericardial effusion, pleural effusion, and ascites

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations.

The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 6).

Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) (%) (%) (%) (%) Hematology Thrombocytopenia 36 47 57 47 (platelet count decreased) Neutropenia (ANC decreased) Leukopenia (WBC decreased) Anemia (Hgb decreased) Lymphopenia

24 14 9 10

51 35 26 26

55 53 55 37

63 63 34 22

ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any Grade* Grade 3/4 (%) (%) Liver function tests ALT increased 53 8 AST increased 41 4 Alkaline phosphatase increased 37 2 Albumin decreased 28 1 Bilirubin increased 19 1 Pancreatic enzymes Lipase increased 41 15 Amylase increased 3 <1 Chemistry Glucose increased 58 6 Phosphorus decreased 57 8 Calcium decreased 52 1 Sodium decreased 29 5 Glucose decreased 24 0 Potassium decreased 16 2 Potassium increased 15 2 Sodium increased 10 <1 Bicarbonate decreased 11 <1 Creatinine increased 7 <1 Calcium increased 5 0 Triglycerides increased 3 <1 ALT=alanine aminotransferase, AST=aspartate aminotransferase. *Graded using NCI-CTC-AE v 4.0

7

DRUG INTERACTIONS Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

7.1 Drugs That Are Strong Inhibitors of CYP3A Enzymes In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2 Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)].

Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3 Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure.

Monitor patients for signs of reduced efficacy.

7.4 Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis.

At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3 Nursing Mothers It is unknown whether ponatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

8.5 Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%).

In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment.

As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment Iclusig has not been studied in patients with renal impairment.

Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on cycle 1 day 2. The patient experienced fatigue and noncardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion.

In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment.

Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234 For information contact: 1-855-55-ARIAD (855-552-7423) medinfo@ariad.com PB/0513/0019/US

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Faculty Perspectives

SEPTEMBER 2013 • VOLUME 4 • NUMBER 2

™

ADVANCES IN THE TREATMENT OF HEMATOLOGIC MALIGNANCIES

PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris

LETTER

FROM THE

EDITOR

Progress in the treatment of hematologic malignancies has been remarkable over the past decade, primarily due to the introduction of targeted agents, a better understanding of prognostic indicators, and new data on biomarker analysis. There is no doubt that these advances have great potential for improving outcomes; however, hematologists and oncologists who seek to provide state-of-the-art therapy for their patients may be challenged by the rapidly shifting paradigm of care. In 2013, a wealth of new data regarding the treatment of chronic lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndromes, myelofibrosis, and multiple myeloma has been presented at major scientific meetings throughout the world. In this “Faculty Perspectives” newsletter series, we will continue to feature highlights from several of these meetings, along with perspectives from highly respected thought leaders in the field, which will provide valuable practice implications for the management of your patients with hematologic malignancies.

Sincerely, Paul Richardson, MD RJ Corman Professor of Medicine Harvard Medical School Clinical Director Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts

Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

FACULTY

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano

Jennifer Brown, MD, PhD Director, Chronic Lymphocytic Leukemia Center Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts

Web Content Managers David Maldonado Anthony Trevean

Stephanie A. Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/ Rush University Chicago, Illinois

Ruben A. Mesa, MD, FACP Professor and Chair Division of Hematology and Medical Oncology Deputy Director Mayo Clinic Cancer Center Professor of Medicine Scottsdale, Arizona

David P. Steensma, MD, FACP Leukemia Program, Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma

Supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

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FACULTY PERSPECTIVES Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

patient characteristics for MF, MDS, CLL, MM, NHL, and HL and apply the results to create an individualized approach to managing each patient

Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships.

Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with hematologic malignancies.

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of hematologic malignancies.

Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.5 contact hours.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this applicationbased activity provides for 1.5 contact hours (0.15 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-017-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss emerging data and recent advances in the personalized treatment of patients with hematologic malignancies, and integrate key findings into clinical practice • Outline contemporary prognostic and predictive biomarkers and

Corporation, and Sanofi. He does intend to discuss either non-FDAapproved or investigational use for the following products/devices: SAR302503.

Paul Richardson, MD, is on the Advisory Board for Bristol-Myers Squibb, Celgene Corporation, Genmab, Johnson & Johnson, Millennium: the Takeda Oncology Company, Novartis, and Onyx.

He does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

David P. Steensma, MD, FACP, is a Consultant for Celgene Corporation and is on the Advisory Committee for Amgen, Astex, and Boehringer Ingelheim. He does intend to discuss either nonFDA-approved or investigational use for the following products/ devices: EPO, mocetinostat, rigosertib, and SGI-110 for MDS and lenalidomide for non-deletion 5q MDS. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures Karen Cooksey, Medical Writer, has nothing to disclose. She does intend to discuss either non-FDA-approved or investigational use for the following product/devices: brentuximab vedotin, elotuzumab, ibrutinib, idelalisib, lenalidomide, MLN9708, mocetinostat, obinutuzumab, ofatumumab, panobinostat, rigosertib, ruxolitinib, SAR302503, and SGI-110.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose.

Pamela Vlahakis, RN, MSN, CBCN, MLI Reviewer, has nothing to disclose.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13005B.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

Faculty Disclosures Jennifer Brown, MD, PhD, is a Consultant for Celgene Corporation, Genentech, Novartis, Onyx, Pharmacyclics, Inc., Sanofi, and Vertex, and has received research funding from Celgene Corporation and Genzyme. She does intend to discuss either non-FDA-approved or investigational use for the following products/devices: idelalisib and obinutuzumab.

Stephanie A. Gregory, MD, is on the Speakers’ Bureau for Celgene Corporation and Janssen and is Chair of the Data Safety Monitoring Board for Genentech (Protocol GAO4753g). She does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

Ruben A. Mesa, MD, FACP, has received research funding from Celgene Corporation, Genentech, Gilead Sciences, Inc, Incyte

For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net.

Estimated time to complete activity: 1.5 hours Date of initial release: September 13, 2013 Valid for CME/CPE/CE credit through: September 13, 2014

Updates from ASCO, EHA, and ICML 2013 Introduction Recently, researchers from around the world gathered at 3 key meetings: (1) the Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, on May 31–June 4, 2013; (2) the 18th Congress of the European Hematology Association (EHA), held in Stockholm, Sweden, on June 13–16, 2013; and (3) the 12th International Conference on Malignant Lymphoma (ICML), held in Lugano, Switzerland, on June 19–22, 2013. After the meetings, Paul Richardson, MD, David P. Steensma, MD, FACP, and Jennifer Brown, MD, PhD, from Dana-Farber Cancer Institute, Stephanie A. Gregory, MD, from Rush University Medical Center, and Ruben A. Mesa, MD, FACP, from the Mayo Clinic reviewed important data from abstracts and presentations regarding the treatment of myelofibrosis (MF), chronic lymphocytic leukemia (CLL), myelodysplastic syndromes (MDS), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL). This supplement provides these experts’ key take-home messages for community oncology practices.

MYELOFIBROSIS

MF, which belongs to the class of hematologic malignancies known as myeloproliferative neoplasms, may be primary, secondary to polycythemia vera (PV), or secondary to essential thrombocythemia (ET).1 The disease is typically characterized by splenomegaly, burdensome symptoms, progressive bone marrow fibrosis, and shortened survival, and has a poor prognosis with limited treatment options.2,3 Although allogeneic stem cell transplant (allo-SCT) may cure MF, the procedure is associated with significant morbidity and transplant-related mortality and is feasible only in young individuals with poor prognostic factors.4 The enlarged spleen and debilitating symptoms of MF are linked to dysregulated signaling in the Janus kinase (JAK) pathway. This dysregulation may be caused by various mechanisms and mutations, such as the JAK2 V617F mutation.5,6 In 2005, the 2 V617F mutation was discovered in approximately 50% of patients with primary MF, as well as in 95% of patients with PV and 50% of patients with ET.7

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Ruxolitinib In November 2011, the US Food and Drug Administration (FDA) approved ruxolitinib, an oral JAK1 and JAK2 inhibitor, for the treatment of patients with intermediate or high-risk MF, including primary MF, post–PV MF, and post-ET MF.8 In the two phase 3 COMFORT (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment) trials, ruxolitinib was shown to reduce spleen volume and improve MF-related symptoms and quality of life, and prolonged survival compared with placebo (COMFORT-I)9 and best available therapy (COMFORT-II), which included hydroxyurea, interferon-alpha, or various sequential therapies.10,11 The primary and key secondary end points were both met: the proportion of patients achieving a response (defined as a ≥35% reduction in spleen volume) at week 48 (ruxolitinib, 28.5%; best available therapy, 0%; P<.0001) and week 24 (31.9% and 0%; P <.0001), respectively.11 Ruxolitinib 3-Year Update. At EHA, a 3-year update of the efficacy and safety findings of the COMFORT-II study was presented by Vannucchi and col-

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Figure 1. Change in bone marrow fibrosis grade: ruxolitinib vs hydroxyurea.15 Ruxolitinib Hydroxyurea 80

24 Months

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leagues. The long-term follow-up data showed that ruxolitinib provided rapid reductions in splenomegaly that were sustained for â&#x2030;Ľ3 years of treatment in the majority of patients. Overall, 75 patients (51.4%) treated with ruxolitinib achieved a â&#x2030;Ľ35% reduction from baseline in spleen volume, and reductions in spleen volumes were sustained with continued ruxolitinib therapy. At the time of data cutoff, the median duration of spleen response had not yet been reached. Ruxolitinib was well tolerated, with 45.2% of patients remaining on study after >3 years of therapy, and no newly reported or unexpected adverse events (AEs) have occurred. Longer follow-up (median, 151 weeks) continues to suggest a survival advantage with ruxolitinib treatment compared with best available therapy. Despite the fact that approximately half the patients initially randomized to best available therapy crossed over to ruxolitinib, there was a 52% reduction in risk of death in the ruxolitinib arm compared with best available therapy (HR=0.48; 95% CI, 0.28-0.85; log-rank P=.009).12 Perspective The COMFORT II trial compared ruxolitinib to best alternative therapy, which largely employed all of the current therapies we had used for MF, or all the therapies that had been used prior to JAK2 inhibition. What was quite interesting is that they continue to see the indication of a survival benefit for these patients, now 3 years out from the conclusion of the trial. In addition, there was nothing suggesting cumulative toxicity for patients receiving this agent. This is very important in terms of long-term management of patients with this therapy. It is also encouraging that many patients remained on ruxolitinib and showed signs of durable responses this far out. Overall, I would say these results are quite favorable, especially since the comparison group had received best alternative therapy.

-Ruben A. Mesa, MD, FACP

Ruxolitinib and Bone Marrow Fibrosis. Bone marrow fibrosis (ie, accumulation of reticulin and/or collagen fibers, possibly mediated by clonal cell-derived cytokines and inflammatory stromal reactions) is a key marker of worsening disease in patients with MF. Standard pharmacotherapy has not been shown to improve bone marrow fibrosis; the only proven treatment option is bone marrow transplantation.13,14 Data presented both at ASCO and at EHA by Kvasnicka and colleagues suggest that long-term treatment with ruxolitinib may stabilize or reverse bone marrow fibrosis.15,16 Results from an exploratory analysis (N=68) of bone marrow fibrosis data from an ongoing phase 1/2 single-arm, open-label trial showed

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that fibrosis of the bone marrow was stabilized or reversed after 24 and 48 months of ruxolitinib treatment in the majority of patients with MF (Figure 1).15 For comparison, bone marrow fibrosis grading was also determined in a separate set of biopsy specimens from 41 patients treated with hydroxyurea monotherapy. A comparable effect on bone marrow fibrosis was not seen with hydroxyurea treatment.

In another comparative analysis, bone marrow fibrosis grading was determined in a set of biopsy specimens from 160 patients treated with best available therapy, which included not only hydroxyurea monotherapy (48%), but also watchful waiting (21%), interferon-alfa (7%), or various other therapies as monotherapy or in combination (corticosteroids, androgens, melphalan, busulfan, thalidomide, splenic irradiation).16 Results were similar to those with hydroxyurea monotherapy. At 24 and 48 months, 62% and 75% of patients receiving best available therapy showed worsening of bone marrow fibrosis, respectively.

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Since the start of testing of JAK2 inhibitors, the issue of whether these agents can have an impact on bone marrow changes has been an important subject of discussion. In other words, is there evidence that these drugs are impacting the natural history of the disease in other biological ways in addition to the demonstrated improvement in splenomegaly symptoms and even survival? This analysis was very interesting because it demonstrated that with long-term use of ruxolitinib, there is a clear signal that patients could potentially experience either a stabilization or improvement in bone marrow fibrosis. Furthermore, compared with a historical control group of patients treated with other MF therapies, ruxolitinib seemed to have a more significant impact on reduction of bone marrow fibrosis and a greater degree of stabilization of fibrosis.

Overall, these results imply that ruxolitinib has a meaningful benefit for the long term and that there is a biological effect that is demonstrable in the bone marrow. It is important to note, however, that this is a lengthy process.

Given the fact that it may take up to 1 year for allo-SCT to produce significant improvements in marrow fibrosis, it is expected that medical therapy may take 2 to 3 years to significantly impact marrow histology.

-Ruben A. Mesa, MD, FACP

SAR302503 SAR302503 (previously TG101348) is an oral, selective JAK2 inhibitor under investigation for the treatment of MF. SAR302503 is being evaluated in a phase 2 study (N=31) of the efficacy and safety of daily oral doses of 300 mg (n=10), 400 mg (n=10), and 500 mg (n=11) in patients with intermediate-2 or high-risk MF. Results after 3 cycles, which were reported previously,17 showed that a spleen response (defined as spleen reduction of at least 35%) was seen in 30% of patients (3/10) in the 300-mg group, 50% (5/10) in the 400-mg group, and 64% (7/11) in the 500-mg group. Updated results were reported at both ASCO and EHA by Pardanani and colleagues, and showed that spleen response rates at the end of 6 cycles of treatment were 30% (3/10) in the 300-mg group, 60% (6/10) with 400 mg, and 55% (6/11) with 500 mg.18,19 SAR302503 reduced baseline constitutional symptoms at the end of cycle 3 in all dose groups, with the greatest symptom responses seen for night sweats in 14/15 patients (93%), itching 10/14 (71%), early satiety 10/18 (56%), and abdominal pain 10/18 (56%). The most commonly reported AEs across all doses were grade 3/4 anemia (58%), grade 3/4 diarrhea (13%), and grade 3/4 thrombocytopenia (16%). No cases of grade 3/4 neutropenia were seen.18,19 Perspective SAR302503 is the JAK2 inhibitor that is the most developed after ruxolitinib for the treatment of MF. Pardanani and colleagues reported on the efficacy and tolerability of SAR302503 at 3 different doses in this phase 2 trial, and reported that it was active in terms of both splenomegaly and symptomatic control. The safety profile was most prevalently impacted by gastrointestinal toxicity. However, the incidence of grade 3/4 toxicities was low and these AEs were frequently manageable. As with other JAK2 inhibitors, treatment-

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FACULTY PERSPECTIVES related cytopenias were prevalent, hence, the effort to best characterize the dose/response by dosing intensity treatment group.

-Ruben A. Mesa, MD, FACP

CHRONIC LYMPHOCYTIC LEUKEMIA

The American Cancer Society estimates that in 2013, approximately 15,680 patients will be diagnosed with CLL and 4580 will die from the disease.20 Although CLL remains incurable, over the past decade there have been major advances in the understanding of the disease pathophysiology and its treatment.21,22 The most important advances in CLL outcomes have been with combination chemotherapy and then with chemoimmunotherapy.22,23 Idelalisib Phosphatidylinositol 3-kinase delta (PI3Kδ) is a molecular target that is critical for the activation, proliferation, and survival of B lymphocytes. PI3Kδ signaling is hyperactive in many B-cell leukemias and lymphomas and drives proliferation, survival, and trafficking to lymphoid tissue.24 Final results of a phase 1 study of idelalisib (GS-1101), an oral, selective inhibitor of PI3Kδ, as monotherapy in 54 patients with relapsed or refractory CLL were reported by Brown and colleagues at ASCO. Patients were treated continuously for up to 48 weeks with idelalisib as a single agent from a 50- to 350-mg/dose once or twice daily in 28-day cycles, although 10 patients received the 300-mg dose once daily in 28-day cycles. Patients had received a median of 5 prior therapies (range, 2-14), and 70% of patients were refractory to their most recent prior regimen. Patients were exposed to idelalisib for a median of 9 months (0-41+), with 25 patients (46%) completing the primary study and 23 patients (43%) enrolling in an extension study. The overall response rate (ORR) was 72% (including 33% who had nodal response with lymphocytosis). The median time to first response was 1.9 months (range, 0.9-12.9). The median progression-free survival (PFS) was 17.1 months and the median duration of response was 18 months. Idelalisib was generally well tolerated. AEs associated with the drug included elevated liver function tests that were asymptomatic and resolved, diarrhea, and rash. Low neutrophil counts and infections, particularly pneumonia, were also observed.25 Perspective Idelalisib was the first PI3Kδ inhibitor to be tested in CLL and has shown very promising activity in relapsed/refractory patients. The population in this study was extremely heavily pretreated, and 70% were refractory to their last regimen, which is more refractory than we see in most studies. However, the response rate was still quite high, and the PFS, even in the phase 1 study, was 17 months. If you look just at patients treated at what was selected as the phase 2 dose, the PFS is even longer at about 29 months. This drug is now in 3 randomized registration trials.

-Jennifer Brown, MD, PhD

Idelalisib was the first PI3Kδ inhibitor to be tested in CLL and has shown very promising activity in relapsed/refractory patients.

Results of a phase 2 study of idelalisib in combination with rituximab in 64 treatment-naive patients (≥65 years of age) with CLL or small lymphocytic lymphoma were presented by O’Brien and colleagues at ASCO 2013. Patients received idelalisib 150 mg twice daily for 48 weeks and rituximab 375 mg/m2 once weekly for 8 weeks. A primary assessment was conducted during the 8th week, and 62 patients with improving or responding disease were enrolled for the extension study. After the completion of a 24-month period, results indicated an ORR of 97%, including complete responses (CRs) in 19% and partial responses (PRs) in 78%. In addition, among the 9 patients with reported chromosome abnormalities, 3 patients reported CRs and 6 reported PRs. A 93% PFS rate was reported in all patients, and a 100% PFS in 9 patients who had high-risk cytogenetics. Overall, 33% of patients in the primary and extension studies experienced grade 3 diarrhea and/or colitis. Grade 3 or higher pneumonia occurred in 17%, transaminase elevations in 23%, and neutrope-

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nia in 28%. Of the patients who discontinued therapy due to AEs, 5 did so because of respiratory events in the first 24 weeks, and 5 did so because of diarrhea/colitis during the extension study. Other causes of discontinuation were anemia and elevated transaminases.26 Perspective O’Brien and colleagues provided us with the first upfront data on idelalisib, which was given in combination with rituximab in this study. These were previously untreated patients with CLL, and the response rate to therapy was very high at 97%. The investigators also evaluated the impact of treatment on patients with high-risk cytogenetics (del [17p]) and found that these individuals responded as well as the rest of the population. This is not typical for current CLL therapies, so the results of this study are very encouraging. In general, idelalisib is well tolerated; it may cause some diarrhea and elevated liver function, but these AEs are typically manageable.

-Jennifer Brown, MD, PhD

Obinutuzumab (GA101) is a glycoengineered, type II anti-CD20 antibody that is being investigated in combination with chlorambucil for the treatment of CLL. Obinutuzumab Plus Chlorambucil Obinutuzumab (GA101) is a glycoengineered, type II anti-CD20 antibody that is being investigated in combination with chlorambucil for the treatment of CLL. Updated results of a phase 3 multicenter, open-label, randomized three-arm study (CLL11) of obinutuzumab were reported by Goede and colleagues at ASCO. In CLL11, the combination of obinutuzumab plus chlorambucil was compared with the combination of rituximab plus chlorambucil (a standard chemotherapy) and with chlorambucil alone in 589 patients with CLL who had preexisting comorbidities. Responses are shown in Figure 2.27 The addition of obinutuzumab to chlorambucil led to a statistically significant reduction in the risk of disease progression or death of 86% (HR=0.14; P≤.0001). The median PFS improved by more than 1 year from 10.9 months for chlorambucil alone to 23 months for obinutuzumab plus chlorambucil.

The addition of rituximab to chlorambucil significantly reduced the risk of disease progression or death during study follow-up by 68% (HR=0.32; P≤.0001). Median PFS was 10.8 months for chlorambucil versus 15.7 months for rituximab plus chlorambucil. The most common grade 3/4 AEs seen with the combination of obinutuzumab and chlorambucil were neutropenia (34%), infusion-related reactions (IRRs, 21%), and infections 6%. The incidence and severity of IRRs decreased dramatically after the first infusion and no serious reactions have been reported beyond the first infusion. The most common toxicities seen with the combination of rituximab and chlorambucil were neutropenia (25%), infections (8%), and IRRs (4%).27 Perspective Obinutuzumab is a novel CD20 antibody that works by a different mechanism of action than the CD20 antibodies already approved for CLL (rituximab and ofatumumab). This agent is glycoengineered, which results in enhanced antibody-dependent cellular cytotoxicity. It also has a type-2 mechanism that is not dependent on the patients’ immune system, which is often impaired in CLL. This was the first report from the phase 3 registration trial of obinutuzumab. Although the investigators did not make a direct comparison between rituximab and obinutuzumab, a report on this is expected later this year. However, the CR rate with obinutuzumab was greatly improved over the CR rate seen with chlorambucil alone. An interesting observation is that a significant number of patients in this trial treated with obinutuzamab plus chlorambucil showed no minimal residual disease, which is not commonly seen with chlorambucil alone. The data from this trial are not yet mature, so we would expect that the PFS rates will be even better in later reports.

-Jennifer Brown, MD, PhD

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Figure 2. Responses observed with obinutuzumab plus chlorambucil vs rituximab plus chlorambucil vs chlorambucil alone.27 80

75.5%

ORR CR

65.9%

Patients (%)

60

40 30.2% 22.2% 20 8.3% 0% 0

Obinutuzumab + Chlorambucil

Rituximab + Chlorambucil

Chlorambucil Alone

CR indicates complete response; ORR, objective response rate.

Ofatumumab Ofatumumab is a CD20-directed cytolytic monoclonal antibody approved by the FDA in 2009 for the treatment of patients with CLL refractory to fludarabine and alemtuzumab. At ASCO, Castro and colleagues presented results of a phase 2, single-arm study evaluating ofatumumab in combination with high-dose methylprednisolone for the treatment of 21 patients (median age, 63 years [range, 46-76], median of 3 prior therapies, 24% had unfavorable cytogenetics, 76% had CLL cells that expressed unmutated IgVH genes or high levels of ZAP-70, 24% were fludarabine refractory) with relapsed or refractory CLL. At 2 months after completion of therapy, the ORR was 81% (17/21) including 5% CR (1/21), 10% nodular PR (2/21), and 67% PR (14/21). The median follow-up time was 12 months (range, 5-23). The median PFS time was 9.1 months and the median treatment-free survival time was 11.5 months.

Treatment was well tolerated. The majority of AEs were grade 1 or 2, including insomnia, anxiety, fatigue, and infusion reactions. Grade 3 AEs included neutropenia (19%), thrombocytopenia (5%), hyperglycemia (71%), nonmelanoma skin cancer and other skin lesions (19%), as well as acute coronary syndrome, atrial fibrillation, renal calculi, pneumonia, and hypocalcemia (1 patient each). There were no grade 4 toxicities.28 Perspective Methylprednisolone is a drug that has activity in relapsed/refractory and high-risk CLL. This drug is typically given in combination with rituximab, so these investigators took a novel approach by combining methylprednisolone with ofatumumab. The patients in this study had a median of 3 prior therapies and about 25% had unfavorable cytogenetics. Thus far, the data look pretty good; the PFS rate seen with this regimen is fairly long for a relapsed/refractory, high-risk CLL population. In general, one advantage to using a steroid-antibody combination such as this is that it can often be given to patients who could not tolerate standard chemotherapy.

-Jennifer Brown, MD, PhD

MYELODYSPLASTIC SYNDROME

The MDSs are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias that progress to acute myeloid leukemia (AML) with myelodysplastic features when blood or bone marrow blasts reach or exceed 20%. Approximately 50% of patients with MDS have a detectable cytogenetic abnormality, most commonly a deletion of all or part of chromo-

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some 5 or 7, or trisomy 8.29 Patients with MDS are classified by the International Prognostic Scoring System (IPSS) into low-, intermediate-1 (int-1)–, intermediate-2 (int-2)–, and high-risk groups based on the percentage of marrow blasts, number of cytopenias, and bone marrow cytogenetic findings.

Among patients with lower-risk (low or int-1) MDS, refractory anemia is the principal therapeutic challenge.30 Therefore, the mainstay of treatment for MDS has traditionally been supportive care, including the use of erythropoiesis-stimulating agents (ESAs) to improve anemia.29 However, ESAs yield only 40%-50% response rates.30 In recent years, several therapeutic agents have been approved for the treatment of patients with MDS, including lenalidomide and the azanucleosides (azacitidine and decitabine), with several promising new agents also under investigation.

Lenalidomide Lenalidomide is FDA approved for the treatment of patients with transfusion-dependent anemia due to low- or int-1–risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Previous studies have shown that lenalidomide allows independence from red blood cell (RBC) transfusions in about 25% of patients with ESA-resistant (or ESA-relapsing), transfusion-dependent, lower-risk MDS without deletion 5q,30 and that a gene expression signature can predict response.31 At both ASCO and EHA, Toma and colleagues presented results from a randomized, open-label phase 2 study of lenalidomide plus erythropoietin versus lenalidomide alone in RBC transfusion-dependent patients (N=132) with lower risk (ie, IPSS scores low or int-1) MDS who did not have deletion 5q and who were resistant to erythropoietin.32,33 The primary end point was erythroid response (hematologic improvement–erythroid [HI-E]), as defined by the 2006 International Working Group response criteria in myelodysplasia.34 Among the 129 patients evaluable for response, 23.4% of patients receiving lenalidomide alone achieved HI-E versus 40.0% of patients receiving lenalidomide plus erythropoietin. In addition, 14.1% of patients receiving lenalidomide alone achieved RBC transfusion independence versus 24.6% of patients receiving lenalidomide plus erythropoietin. Among the 99 patients who completed 4 treatment cycles, 30.6% of patients receiving lenalidomide alone achieved HI-E versus 52.0% of patients receiving lenalidomide plus erythropoietin. Furthermore, 18.4% of patients receiving lenalidomide alone achieved RBC transfusion independence versus 32.0% of patients receiving lenalidomide plus erythropoietin (Figure 3).32,33 AEs were similar in the 2 groups. A 29-gene expression profile signature predicting HI-E to lenalidomide plus erythropoietin versus lenalidomide alone was identified and a polymorphism in the CRBN gene was significantly associated with HI-E in the entire cohort (P=.034).

Perspective This was a randomized trial of lenalidomide with or without erythropoietin in patients who did not have deletion 5q. The reason this is important is because while lenalidomide works really quite well in those patients with lower-risk MDS who have this deletion, outside of that population, there’s a subset of patients who respond, but it is difficult to predict who those patients will be in advance.

This study was conducted for 2 reasons: (1) to ascertain whether lenalidomide could resensitize patients to erythropoietin and (2) to determine whether there was some sort of gene signature that predicted which patients without deletion 5q would respond better to lenalidomide. The investigators found that with lenalidomide alone, there was a transfusion independence rate of 14%, which is low but meaningful in lower-risk patients who often have few options. When patients were given a combination of lenalidomide plus erythropoietin, responses were a little better.

There was, in fact, a gene signature that predicted response to the combination therapy, as well as a cereblon polymorphism that predicted response to lenalidomide. That is interesting biologically, but there is not currently a clinically available test for either the gene expression pattern or the polymorphism. Also, these are not practice-changing results because even though the cereblon polymorphism was associated with significantly better responses, there were still patients who did not have the polymorphism who responded, as well as patients who had it and did not respond. So the mys-

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Azanucleosides Two azanucleosides, azacitidine and decitabine, are FDA approved for the treatment of MDS; however, azanucleoside treatment is limited by prohibitive AEs (mainly myelosuppression, as manifested by thrombocytopenia, neutropenia, and anemia) or the lack of sustained benefit. In 2008, Borthakur and colleagues published results of 14 patients with MDS who achieved a 28% ORR (including 3 CRs) with decitabine after lack of response to azacitidine.35 At ASCO, Komrokji and colleagues presented results of their retrospective investigation of cases of sequential azanucleoside treatment that were identified through the Moffitt Cancer Center MDS database. Two groups of patients were identified; Group 1 (32%) had received decitabine after azacitidine failure and Group 2 (68%) had received azacitidine after decitabine failure. A total of 39 MDS patients who received treatment with both azanucleosides were identified. Complete records were available in 31 patients, including 21 patients in Group 1 (decitabine after azacitidine) and 10 patients in Group 2 (azacitidine after decitabine). Results showed that response rates were higher in patients who received decitabine followed by azacitidine (40% vs 19%) and that the rate of transformation to AML was lower for patients who received decitabine followed by azacitidine (20% vs 29%). The median overall survival was also higher for patients who received decitabine followed by azacitidine (100 months from diagnosis), compared with patients who received azacitidine followed by decitabine (48 months).36 Perspective Most patients with higher-risk MDS are treated at some point with azacitidine or decitabine. These drugs are very similar chemically and have virtually the same intracellular effects on gene expression and DNA methyltransferase binding. This study sought to answer the question: if you use one of these 2 agents and it doesn’t work, is there a role for trying the other? In my own clinical experience, I have not seen a patient respond to a second azanucleoside after the first one failed, whether going from azacitidine to decitabine or vice versa. A French study also suggested that this was not a useful strategy. However, the investigators from Moffitt, like those from MD Anderson who looked at this issue 5 years ago, did report that there were a significant number of patients that responded to one agent after the other one had

This study sought to answer the question: if you use one of these 2 agents and it doesn’t work, is there a role for trying the other? failed. Among the patients who received decitabine followed by azacitidine in this study, 40% of them showed a response, which is high enough that it may make us rethink this strategy. It is important to note, however, that the duration of response to the second drug was generally only a few months. This is not a curative therapy, but it might give a little bit of extra mileage out of an azanucleoside. The bottom line is that when azacitidine or decitabine fails, we don’t have a lot of other good options for our patients who are not eligible for transplant. The results of this study at least suggest that it may be worth it, in some patients, to do a trial of a second azanucleoside if the first one fails and if the patient is not a candidate for transplant and doesn’t have access to a clinical trial.

-David P. Steensma, MD, FACP

Rigosertib Rigosertib, a novel small molecule inhibitor of both PI3K and polo-like kinase, is being developed in both oral and intravenous (IV) forms as a treatment for hematologic diseases and solid tumors. Interim data from the randomized phase 2 ONTARGET study, which is evaluating oral rigosertib as a single agent (administered either intermittently [for 2 of 3 weeks] or continu-

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Figure 3. RBC transfusion independence after 4 cycles: lenalidomide plus erythropoietin vs lenalidomide alone.32,33

40 32.0%

Patients (%)

tery of which patients without del 5q will respond to lenalidomide remains partly unsolved.

-David P. Steensma, MD, FACP

18.4%

20

0

Lenalidomide Plus Erythropoietin

Lenalidomide Alone

RBC indicates red blood count.

ously) in transfusion-dependent lower-risk MDS patients, were presented at ASCO. In the ONTARGET study, 50% (13/26) of the evaluable patients in the intermittent-dosing group and 25% (2/8) of the evaluable patients in the continuous-dosing group achieved transfusion independence (defined as no RBC transfusions for at least 8 consecutive weeks). None of the responders had a deletion 5q upon cytogenetic evaluation. Onset of transfusion independence ranged from 1 to 24 weeks following the initiation of rigosertib dosing, and the duration of transfusion independence ranged from 8 to >48 weeks, with 2 patients continuing to benefit from therapy >9 months after initiating rigosertib treatment. Eleven of the 13 transfusion-independent patients in the intermittent-dosing arm received ≥1 injection of ESAs during the time of oral rigosertib administration, and the patterns of hemoglobin responses observed in a few patients suggest a possible synergy between oral rigosertib and ESAs. Rigosertib was generally well tolerated except for a high incidence of grade ≥2 urinary AEs. In the continuous-dosing arm of the study, grade ≥2 urinary AEs (dysuria, hematuria, cystitis, and urinary urgency) were observed in 5 of the first 9 patients. Therefore, the study protocol was amended to allow for all patients to be treated with intermittent dosing, with the option of dose interruption/reduction resulting in a much lower frequency of urinary AEs. The most frequent urinary AEs in the intermittent-dosing arm were grade ≥2 urinary urgency/frequency (38%), grade ≥2 dysuria (15%), and hematuria (15%).

Intermittent grade 3/4 neutropenia (n=2) was also observed (1 patient per grade). Median onset of grade ≥2 AEs in the intermittent-dosing group was 28 weeks versus 12 weeks in the continuous-dosing group. Median duration of treatment in the intermittent-dosing group has not yet been reached (>48 weeks vs 24 weeks in the continuous-dosing group). Renal function was unaffected and gastrointestinal AEs and fatigue were infrequently observed.37 Perspective There is a 300-patient randomized trial under way in which IV rigosertib is being administered as a 72-hour infusion every 2 weeks in patients who were treated with azacitidine or decitabine and either didn’t respond or lost their response to the azanucleoside. The control group in that study is either supportive care or low-dose cytarabine. It will be interesting to see the results, which will hopefully determine whether rigosertib can improve survival when given to higher-risk MDS patients in a second-line setting.

In this ONTARGET trial, the investigators chose to use a more convenient oral form of rigosertib in patients with lower-risk MDS. They reported that in a relatively small number of patients, there was some hematologic improvement. However, this agent appeared to be very irritating to the bladder, so partway through the trial, they amended the protocol so that patients could receive intermittent dosing rather than continuous dosing, which did reduce the incidence of this AE. This oral drug could turn out to be helpful for some patients with lower-risk MDS. Still, I think the urinary toxicity is somewhat con-

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CONTINUING EDUCATION cerning because many MDS patients are older men with prostate problems who already have urinary difficulties.

-David P. Steensma, MD, FACP

Mocetinostat Mocetinostat, an oral isotype-selective histone deacetylase inhibitor, is being evaluated in an open-label phase 2 study in combination with the demethylating agent azacitidine in 28 patients with MDS (median age, 72 years; 54% had marrow blast counts >10%; 64% were intermediate or high risk; 50% had received >1 prior therapy [none had received prior azacitidine]). The ORR was 61%, including 50% who achieved a CR or a CR with incomplete recovery (CRi), and 11% who achieved HI. Of the patients with int-2 or highrisk MDS, 9/14 (64%) achieved CR or CRi. The median OS was 12.9 months (range 1.9-62.0). On-study transfusion independence was achieved in 36% (8/22) of patients. Clinically meaningful reductions in bone marrow blasts were seen by cycle 2, with continued improvement in cycle 3. The most common severe side effects among all study participants included fatigue (23%), nausea (22%), diarrhea (17%), and vomiting (14%).38 Perspective There is a number of deacetylase inhibitors that are being, or have been, evaluated in MDS, including mocetinostat, which used to be known as MGCD0103. In this trial, because everyone received combination therapy, it is difficult to ascertain how many of the responses seen were due to azacitidine versus the combination regimen. However, the investigators did observe that 50% of patients achieved a reduction in bone marrow blasts and some also had hematopoietic recovery. That’s a pretty high rate. I think that mocetinostat needs to be compared in a randomized fashion to azacitidine alone to get a better idea of its clinical activity, just like the vorinostatazacitidine combination that is being compared with azacitidine alone in the US/Canadian S1117 Intergroup trial. Right now, we don’t know if mocetinostat will be any more effective than vorinostat, panobinostat, pacrinostat, or any of the other histone deacetylase inhibitors currently under investigation in MDS. -David P. Steensma, MD, FACP

The investigational agent MLN9708 (ixazomib citrate) is the first oral proteasome inhibitor in the boronate peptide class with reported clinical activity in MM. SGI-110 SGI-110 is a second-generation hypomethylating agent (formulated as a dinucleotide of decitabine and deoxyguanosine) delivered as a subcutaneous injection that allows a longer half-life and more extended decitabine exposure than IV decitabine infusion. At EHA, O’Connell and colleagues presented results of a randomized phase 1 dose escalation study with 2 different regimens of SGI-110 in 15 intermediate- or high-risk MDS patients (median 74 years of age [range, 46-82]; median of 2 prior therapies) who had previously failed treatment with azacitidine or decitabine. Responses were observed in 5 patients for an ORR of 33% with reported response duration of 28 to 224 days.

Patients who responded had higher baseline median bone marrow blast counts (16.5%) than patients who did not respond (5%). Treatment was well tolerated; the most commonly reported nonhematologic AEs (mostly grade 1) were injection site pain and diarrhea.39 Perspective SGI-110 is interesting in that it is almost like a precursor drug of decitabine.

Basically, it is decitabine conjugated to another nucleoside, which seems to allow for longer drug exposure, prolonged half-life, and deeper methylation changes across the genome. Whether that’s going to translate into a clinical benefit over existing azanucleosides, however, remains to be seen. I think

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one take-home from this study is that there were patients who had previously been treated with decitabine who in fact did respond to SGI-110, suggesting that this investigational agent may be a little more potent than decitabine itself.

-David P. Steensma, MD, FACP

MULTIPLE MYELOMA

The American Cancer Society estimates that this year, MM will be diagnosed in 22,350 individuals (12,440 men and 9910 women), and will result in 10,710 deaths.20 Novel and active combination regimens that are well tolerated as long-term therapy are required for elderly patients with MM, including many who are ineligible for autologous stem cell transplantation (ASCT).

MLN9708, Lenalidomide, and Dexamethasone The investigational agent MLN9708 (ixazomib citrate) is the first oral proteasome inhibitor in the boronate peptide class with reported clinical activity in MM. At EHA, Richardson and colleagues presented subset analysis results (comparing elderly vs younger patients) of a phase 1/2 study of oral MLN9708 (dosed weekly) plus lenalidomide-dexamethasone in both transplant-eligible and transplant-ineligible patients with previously untreated MM. Preliminary response data showed clinical activity across the age groups (Table 1). A total of 3 patients had disease progression, including 0, 3, and 2 patients aged <65, ≥65, and ≥75 years, respectively.40 The incidences of common (≥30% of patients overall), all-grade, all-cause AEs at the recommended phase 2 dose were similar across the age groups (Table 2). There were 2 on-study deaths, 1 due to cardiorespiratory arrest after abdominal surgery in an 86-year-old patient (considered unrelated to the study drug by the investigator) and 1 due to drug-related respiratory syncytial virus pneumonia in a 68-year-old patient.40 Perspective The combination of ixazomib citrate and lenalidomide and dexamethasone in the upfront treatment of myeloma demonstrated very exciting results with encouraging response rates for this “all oral” regimen, an ORR of approximately 90% and the very high quality of responses seen as well. In this analysis of our multicenter phase 1/2 study, clinical activity across all age groups and a broadly manageable set of side effects was demonstrated. Encouragingly, rates of peripheral neuropathy were remarkably low and whilst fatigue and gastrointestinal upset remain important side effects of this combination, the overall tolerability of this oral regimen was favorable. Phase 3 studies of this combination are now under way in both the relapsed and upfront settings, with accrual proceeding well. Given the remarkably high quality of responses seen in the upfront setting, it is anticipated that this will be an important combination for myeloma patients in general. Finally, this particular platform of a proteasome inhibitor combined with an immunomodulator demonstrates clinical synergy and further validates this approach, as originally seen with the combination of lenalidomide and bortezomib. It also emphasizes the convenience of an all oral combination, as well as important differences in overall tolerability compared with other regimens.

-Paul Richardson, MD

Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone Carfilzomib is FDA approved for the treatment of MM in patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent. Jakubowiak and colleagues previously published 13-month results of a phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for MM.41 At ASCO, they presented updated (25-month) results (Table 3) from 53 patients who had received a median of 22 cycles (range, 2-24).42 Immunophenotypic CR was achieved in 22/26 of evaluated patients.

Among the patients who achieved stringent CR (sCR), 25% had high-risk cytogenetics. Among the patients who did not proceed to transplant (n=46), the sCR was 59%, CR 70%, ≥near complete response (nCR) 78%, ≥very good partial response (VGPR) 91%, and ≥PR 100%. Over the course of treatment,

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Table 1. Responses to MLN9708 Plus Lenalidomide Plus Dexamethasone by Age Group40

Patients <65 Years of Age (n=31)

Patients ≥65 Years of Age (n=34)

Patients ≥75 Years of Age (n=12)

Fatigue

56%

64%

60%

Diarrhea

44%

54%

60%

18%

Nausea

52%

32%

50%

55%

Constipation

44%

32%

20%

Peripheral edema

36%

36%

20%

Upper respiratory tract infection

32%

32%

10%

Vomiting

32%

21%

40%

Patients <65 Years of Age (n=31)

Patients ≥65 Years of Age (n=34)

Patients ≥75 Years of Age (n=12)

ORR

94%

91%

82%

CR+VGPR

43%

70%

73%

CR

29%

24%

VGPR

13%

45%

CR indicates complete response; ORR, overall response rate, VGPR, very good partial response.

the depth of response improved. Median time to ≥VGPR was 4 cycles (range, 2-17), ≥nCR 4.5 cycles (range, 2-15), and sCR 10 cycles (range, 4-30). Two patients converted to sCR during lenalidomide maintenance. At 2 years, for all patients, the estimated PFS rate was 94% and the overall survival (OS) was 98%. For the subset of patients that achieved an sCR, the PFS rate was 96% and the OS rate was 100%. AE types, rates, and dose modifications during extended treatment were comparable to those previously reported at 13 months, follow-up. There was 1 death off-study due to disease progression.42 Perspective Jakubowiak and colleagues updated at ASCO the results in 53 patients of their highly active combination of carfilzomib, lenalidomide, and low-dose dexamethasone with newly diagnosed myeloma. In this analysis, updated information regarding the quality of response was presented, with the high rate of sCRs seen in patients not proceeding to transplant being especially noteworthy. Consistent with other regimens in this setting, over the course of treatment, depth of response improved. A particularly striking aspect of this analysis was the high quality of responses achieved even as patients proceeded to maintenance with lenalidomide alone, suggesting a durable effect from carfilzomib and commensurate with its pharmacodynamics as a very potent proteasome inhibitor. Importantly, tolerability was favorable with rates of treatment-emergent neuropathy stable at approximately 25% and the incidence of cardiopulmonary toxicity remaining low. Comparative studies of this regimen versus lenalidomide, bortezomib, and low-dose dexamethasone are planned and should provide greater insights into both its activity and tolerability in newly diagnosed patients. Once more, the concept of proteasome inhibition plus immunomodulatory therapy as a synergistic combination in the clinical setting has been validated by these remarkable results.

-Paul Richardson, MD

Elotuzumab, Lenalidomide, and Low-Dose Dexamethasone The humanized monoclonal antibody elotuzumab targets CS1, a protein that is highly expressed on the surface of MM cells, mediates their adhesion to bone marrow stromal cells, and enhances natural killer cell-mediated killing of MM cells primarily via antibody-dependent cell–mediated cytotoxicity.43 Updated results from a small, randomized, open-label phase 1/2 study of elotuzumab (either at a 10-mg/kg dose or a 20-mg/kg dose) in combination with lenalidomide and low-dose dexamethasone in 73 patients with relapsed or refractory MM were reported by Lonial and colleagues at both ASCO and EHA. In the phase 2 cohort, after a median follow-up of 20.8 months, the median PFS was 33 months and the ORR was 92% for patients who received 10 mg/kg (n=36) and the median PFS was 18.6 months and the ORR was 76% for those who received 20 mg/kg (n=37). The most common grade 3/4 toxicities for the 10-mg/kg and 20-mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%). Most treatment-emergent AEs occurred within 18 months of initiating therapy. Across all patients in the study, 15 patients discontinued due to AEs (none after 18 months of treatment). Four second primary malignancies occurred (none were reported after 18 months of treatment).44,45

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Table 2. Toxicities* Reported With MLN9708 Plus Lenalidomide Plus Dexamethasone by Age Group40 Adverse Event

*Common (≥30% of patients overall), all-grade, all-cause AEs at the recommended phase 2 dose.

Table 3. Responses With Carfilzomib, Lenalidomide, and LowDose Dexamethasone: 13-Month vs 25-Month Follow-Up41,42 13-Month Follow-Up

25-Month Follow-Up

sCR

42%

53%

CR

62%

64%

nCR

62%

72%

VGPR

81%

87%

PR

98%

98%

CR indicates complete response; nCR, near complete response; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.

Perspective Lonial and colleagues updated the results both at ASCO and EHA of this important study in which the combination of elotuzumab, lenalidomide, and low-dose dexamethasone have previously shown striking results in a phase 1 trial. This subsequent randomized, open-label phase 2 study evaluated elotuzumab either at a 10-mg/kg dose or a 20-mg/kg dose in combination with lenalidomide, and low-dose dexamethasone in 73 patients with relapsed or refractory MM and demonstrated encouraging PFS, with a median of 33 months (vs approximately 11 months in a similar study of comparable patients previously with lenalidomide and dexamethasone alone) and a remarkably high ORR of 92%. Interestingly, median PFS and ORR were less in those receiving higher-dose elotuzumab. Side effect profiles were nonetheless similar and this combination was generally well tolerated with manageable toxicity.

This combination continues to show considerable promise as an exciting platform for combination therapy utilizing monoclonal antibodies. Elotuzumab is currently a front-running monoclonal antibody in myeloma now being evaluated in phase 3 trials, both in the relapsed and refractory setting as well as in the newly diagnosed setting. The synergy with immunomodulatory therapy is particularly noteworthy. Moreover, current clinical trials are exploring its activity with bortezomib and studies evaluating elotuzumab in combination with both immunomodulatory therapy and proteasome inhibitors (eg, lenalidomide, bortezomib, and dexamethasone plus elotuzumab) are either planned or soon to be under way.

-Paul Richardson, MD

Bortezomib, Panobinostat, and Dexamethasone In a phase 2 single-arm, open-label, multicenter study known as PANORAMA 2, Richardson and colleagues previously evaluated oral panobinostat in combination with bortezomib and dexamethasone in 55 patients with relapsed and bortezomib-refractory MM (PANORAMA 2) and found an ORR of 34.5%, a clinical benefit rate (CBR) of 52.7%, and a median PFS time of 5.4 months.46 At both ASCO and EHA, these investigators presented further results from PANORAMA 2, in which they evaluated clinical response by baseline patient characteristics. With few exceptions, the efficacy

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CONTINUING EDUCATION end points were similar regardless of baseline demographics. A trend was seen toward a higher response rate in patients whose prior bortezomib therapy was not their last line of therapy. However, the numbers are small and did not reach statistical significance. While no trend in response rate was noted, PFS appeared to be longer in those who had progressed within 60 days of their last bortezomib-containing regimen than in those who had progressed while on their last bortezomib-containing regimen. Among patients with adverse cytogenetics (n=14) the ORR was 42.9% and the CBR was 71.4%. The authors concluded that panobinostat, when combined with bortezomib and dexamethasone, recaptured responses in heavily pretreated, bortezomib-refractory MM patients; demonstrated activity regardless of baseline demographics; and was tolerable, with manageable toxicities. While the small patient subgroups limit more definitive conclusions, it appears that patients with high-risk cytogenetics had similar outcomes to the patient population as a whole.

Symptoms of peripheral neuropathy remained relatively unchanged throughout the study.47,48

Brentuximab vedotin is a CD30-targeted antibody-drug conjugate that is FDA approved for the treatment of HL and for the treatment of systemic anaplastic large cell lymphoma (ALCL).

Perspective In the setting of relapsed and refractory MM, in which all patients were bortezomib-resistant, we were encouraged by the results of this relatively large, single-arm multicenter phase 2 trial which observed a response rate of approximately 35%, with 53% of patients enjoying minimal response or better, and an overall median PFS in excess of 5 months. In our updated analyses, the efficacy end points appeared similar regardless of baseline demographics. Of particular note was the activity of the combination in patients with adverse cytogenetics, where we saw an ORR of 43% and a clinical benefit rate of 71%. Recognizing that the size and single arm design of this trial limits interpretation, the construct of a histone deacetylase inhibitor combined with dexamethasone and bortezomib being active in this population is nonetheless supported by these favorable results. Moreover, given that newer histone deacetylase inhibitors with a more manageable side effect profile are now in development, these results do suggest that this approach warrants further study, and results from ongoing phase 3 trials with panobinostat as well as other agents are awaited with great interest.

-Paul Richardson, MD

NON-HODGKIN LYMPHOMA

The American Cancer Society estimates that in 2013, NHL will be diagnosed in 69,740 individuals (37,600 men and 32,140 women), and will result in 19,020 deaths.20

Lenalidomide Plus Rituximab Follicular lymphoma (FL) is the most common indolent NHL and the second most common form of NHL.49 Previously reported results showed activity of lenalidomide plus rituximab in patients with recurrent FL.50 At ICML, Martin and colleagues presented the results of a multicenter, phase 2 study (CALGB 50803; ALLIANCE) of lenalidomide plus rituximab in 66 patients with previously untreated FL. Among the 54 patients evaluable for response, the ORR was 92.6%, including 72.2% CRs and 20.4% PRs. Grade 3/4 AEs included neutropenia (20%), lymphopenia (8%), rash (8%), fatigue (6%), and leukopenia (5%). Grade â&#x2030;Ľ2 AEs included fatigue (25%), infusion reaction (17%), upper respiratory reaction (13%), nausea (8%), constipation (7%), increased ALT (7%), hyperglycemia (7%), hypophosphatemia (7%), pain (6%), oral mucositis (5%), and myalgia (5%). Febrile neutropenia occurred in 1 patient (2%).51 Perspective Although many individuals still die from FL, the life span of patients has increased dramatically over the past several years, to the point where we can

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almost consider this a chronic illness. Going forward, I think that we need to focus on novel, less toxic approaches to treating this subtype of NHL, such as the regimen of lenalidomide plus rituximab evaluated in this trial by Martin and colleagues. It is important to note that the inclusion criteria were for patients with Follicular Lymphoma International Prognostic Index (FLIPI) scores of 0 to 2. Therefore, this was a low-risk group of patients and the question arises whether they even needed treatment. There are other studies looking at lenalidomide plus rituximab in patients who have higher tumor burden and higher FLIPI scores. With that being said, the high CR rate seen with this combination was very impressive for a nonchemotherapeutic regimen.

-Stephanie A. Gregory, MD

Ibrutinib Plus Bendamustine-Rituximab Mantle cell lymphoma (MCL) is an aggressive type of B-cell NHL that usually occurs in older adults.52 In the United States, approximately 5000 new cases of MCL are diagnosed each year; this subtype accounts for approximately 6% to 8% of NHL diagnoses. The average survival time with MCL is significantly shorter than with other types of indolent lymphomas.53 Currently, bortezomib is FDA approved as treatment for patients with MCL who have received at least 1 prior therapy, and lenalidomide is approved for patients whose disease has relapsed or progressed after 2 prior therapies, one of which included bortezomib. Ibrutinib is an investigational, oral Brutonâ&#x20AC;&#x2122;s tyrosine kinase (BTK) inhibitor that has previously demonstrated promising singleagent activity in a phase 2 study in relapsed or refractory MCL: 68% ORR, including 22% CRs.54 In addition, ibrutinib was combined with bendamustine and rituximab in a phase 1 study in relapsed or refractory NHL and results indicated that ibrutinib enhanced the activity of bendamustine-rituximab: in 5 evaluable patients, the ORR was 100%, including 80% CRs.55 At ICML, Dreyling and colleagues described a phase 3 double-blind, placebo-controlled study (SHINE) of ibrutinib in combination with bendamustine-rituximab versus bendamustine-rituximab without ibrutinib that began enrolling patients in the first quarter of 2013. At approximately 200 sites globally, the investigators aim to enroll 520 patients 65 years of age or older who are ineligible for high-dose chemotherapy. Key exclusion criteria include diagnosis or treatment for malignancy other than MCL, requirement for treatment with warfarin or equivalent vitamin K antagonists, and treatment with strong CYP3A4/5 inhibitors. All patients will receive bendamustine-rituximab therapy for 6 cycles; those patients achieving a CR or PR will receive rituximab maintenance for 2 years. In addition to bendamustine-rituximab and rituximab, all patients will receive an oral daily dose of 560 mg ibrutinib or placebo concomitant with the chemotherapy and ongoing as a single agent until disease progression or unacceptable toxicity. The primary objective is to evaluate if the addition of ibrutinib to bendamustine-rituximab will result in prolongation of PFS, with secondary objectives of evaluation of OS, ORR, CR, duration of response, and safety.56 Perspective The regimen being evaluated by Dreyling and colleagues in the SHINE study is a very novel approach to treating newly diagnosed MCL. We already know that bendamustine plus rituximab produces very high ORR and CR rates in patients with MCL who are not eligible for transplant. We also know that rituximab maintenance prolongs OS in these individuals. The addition of the novel BTK inhibitor ibrutinib, which appears to be a promising strategy, will hopefully lead to even better patient outcomes, and we are anxiously awaiting PFS and OS results from this trial.

-Stephanie A. Gregory, MD

Brentuximab Vedotin Brentuximab vedotin is a CD30-targeted antibody-drug conjugate that is FDA approved for the treatment of HL and for the treatment of systemic anaplastic large cell lymphoma (ALCL). The most common initial treatment for mature T-cell lymphomas is CHOP, a combination of the drugs cyclophosphamide, doxorubicin, vincristine, and prednisone. At ICML, Oâ&#x20AC;&#x2122;Connor and colleagues described a randomized, double-blind, placebo-controlled, multicenter, global phase 3 study (ECHELON-2) comparing CHOP versus the

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FACULTY PERSPECTIVES combination of brentuximab vedotin and CHP (cyclophosphamide, doxorubicin, and prednisone) in the frontline treatment of patients with CD30+ mature T-cell lymphomas that began enrolling patients in early 2013. The investigators aim to randomize approximately 300 patients 1:1 to receive either brentuximab vedotin and CHP or CHOP for 6 to 8 cycles. Randomization will be stratified by anaplastic lymphoma kinase (ALK)+ sALCL versus other histologic subtypes and International Prognostic Index score (0-1, 2-3, or 4-5).

The target proportion of patients with a diagnosis of systemic ALCL (sALCL) will be 75%. The primary objective is PFS; secondary objectives include safety, OS, and CR. After completion of treatment, patients will be followed for disease progression, medical resource utilization, quality of life, and survival.

Post-treatment stem cell transplant is permitted.57 Perspective CHOP is not the treatment of choice for any T-cell lymphomas with the exception of anaplastic ALK+ T-cell lymphomas. O’Connor and colleagues’s approach of substituting brentuximab for vincristine, thereby creating a novel CHOP-like regimen, is exciting. Although the toxicity profile of brentuximab is typically very good, neurotoxicity can be an issue, which is why the cohort of patients who received this agent did not receive vincristine as part of their treatment. We are hopeful that the results of this trial will provide us with a new, more effective strategy for this hard-to-treat patient population with CD30+ T-cell lymphomas.

-Stephanie A. Gregory, MD

HODGKIN LYMPHOMA

The American Cancer Society estimates that this year, HL will be diagnosed in approximately 9290 individuals (5070 men and 4220 women), and will result in 1180 deaths.20

BEACOPP, which is a very aggressive regimen, is typically used to treat patients with high-risk advanced-stage HL. ABVD vs BEACOPP An intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), has been advocated as the new standard of treatment for advanced HL, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). In 2011, Viviani and colleagues conducted a study in which 331 patients with previously untreated and unfavorable HL received either BEACOPP or ABVD. They found that treatment with BEACOPP resulted in better initial tumor control than ABVD, but the long-term clinical outcome did not differ significantly between the 2 regimens, and severe AEs occurred more frequently in the BEACOPP group than in the ABVD group.58 Given the higher treatment-related morbidity, whether or not BEACOPP should be given to low-risk patients has been a matter of debate. At ICML, Mounier and colleagues presented final results from the LYSA H34 study, which compared 8 cycles of ABVD (n=80) with 4 escalated cycles of BEACOPP (n=70) in 150 patients with low-risk (Interntaional Prognostic Index score of 0-2) HL. They found that 85% of patients receiving ABVD and 90% of patients receiving BEACOPP achieved a CR. Relapses occurred more frequently in the ABVD group (14 in the ABVD group vs 3 patients in the BEACOPP group). Second malignancies occurred in 5 ABVD patients and 1 BEACOPP patient. With a median follow-up of 5.5 years, 7 patients died: 6 in the group receiving ABVD and 1 in the group receiving BEACOPP. Five-year survival outcomes are shown in Table 4.59 Perspective BEACOPP, which is a very aggressive regimen, is typically used to treat patients with high-risk advanced-stage HL. In the LYSA H34 study, the investigators chose to compare the safety and efficacy of this regimen with ABVD (the standard of care in the US) for low-risk advanced-stage patients.

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Table 4. Outcomes at 5 Years: ABVD vs BEACOPP59 ABVD Group (n=80)

BEACOPP Group (n=70)

Hazard Ratio

EFS

62%

77%

0.6

.07

PFS

75%

93%

0.3

.007

OS

92%

99%

0.18

.06

P Value

ABVD indicates doxorubicin, bleomycin, vinblastine, and dacarbazine; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; EFS, eventfree survival; OS, overall survival; PFS, progression-free survival.

It is interesting that the results showed higher response rates and lower relapse rates with BEACOPP compared with ABVD. I do question the increased incidence of secondary malignancies reported with ABVD over BEACOPP. This is unusual, as these events are rarely reported with the use of ABVD. The OS rates at 5 years were not significantly different between the 2 regimens in this trial, so given the higher toxicity associated with BEACOPP in general, ABVD is still the treatment of choice for low-risk advanced-stage patients in the US. -Stephanie A. Gregory, MD

Brentuximab Vedotin In 2011, the FDA granted accelerated approval to brentuximab vedotin (a CD30-targeted antibody-drug conjugate) for the treatment of (1) patients with HL after failure of ASCT or after failure of ≥2 prior multiagent chemotherapy regimens in patients who are not candidates for ASCT, and (2) patients with sALCL after failure of ≥1 prior multiagent chemotherapy regimen.

At ICML, Radford and colleagues presented results from a post hoc analysis comparing PFS achieved with brentuximab vedotin versus PFS achieved with the last prior therapy for each of these patient populations in 2 phase 2 studies (SGN35-003 and SGN35-004). SGN35-003 enrolled 102 patients (median age, 31 years [range, 15-77]; median 3.5 prior therapies [range, 1-13]. At the data cut-off (median follow-up 27 months), 62% of patients achieved longer durations of PFS with brentuximab vedotin than with their most recent prior therapy. SGN35-004 enrolled 58 patients (median age, 52 years [range, 1476]; median 2 prior therapies [range, 1-6]. At the data cut-off (median follow-up 22 months), 66% of patients achieved longer PFS with brentuximab vedotin than with their most recent prior therapy.60 Perspective In the study by Radford and colleagues, single-agent brentuximab was shown to be effective in patients with relapsed HL who were either transplant-ineligible or who had relapsed after transplant, as well as in patients with sALCL. I think the results of this study were interesting and this is a novel approach to treatment in 2 rather unusual patient situations.

-Stephanie A. Gregory, MD

CONCLUSIONS

In the arena of MF, long-term treatment with ruxolitinib is well tolerated and provides rapid, sustained reductions in splenomegaly, may stabilize or reverse bone marrow fibrosis, and may provide a survival advantage compared with best available therapy. SAR302503 also shows promise in the treatment of MF, with response rates at the end of 6 cycles as high as 60%. In CLL, idelalisib has shown activity both as a single agent and in combination with rituximab. Chemoimmunotherapy with obinutuzumab/chlorambucil or with rituximab/chlorambucil significantly prolongs PFS versus chlorambucil alone, and the combination of high-dose methylprednisolone plus ofatumumab is an effective, tolerable, nonmyelosuppressive treatment regimen. For patients with MDS, lenalidomide plus erythropoietin yielded a significantly better erythroid response than lenalidomide alone in lower-risk MDS patients with anemia resistant to ESA treatment alone; intermittent dosing of rigosertib is well tolerated and active in producing transfusion independence in approximately 50% of transfusion-dependent, lower-risk MDS patients. Other promising therapies for MDS include mocetinostat, decitabine followed by azacitidine, and SGI-

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CONTINUING EDUCATION 110. In MM, a number of novel combination regimens are showing activity, including MLN9708-lenalidomide-dexamethasone, carfilzomib-lenalidomidedexamethasone, elotuzumab-lenalidomide-dexamethasone, and bortezomib-panobinostat-dexamethasone. In the NHL arena, combinations including lenalidomide-rituximab, ibrutinib-bendamustine-rituximab, and brentuximab vedotin in combination with CHP are under investigation. In HL, results suggest that both ABVD and BEACOPP are effective in prolonging survival, but more progressions/relapses were observed with ABVD than with BEACOPP. In addition, in heavily pretreated patients with HL, treatment with brentuximab vedotin was associated with a longer duration of remission than that achieved with the last prior therapy in more than 60% of patients.

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38. Luger SM, O’Connell CL, Klimek V, et al. A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS) J Clin Oncol. 2013;31(suppl).

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FACULTY PERSPECTIVES 51. Martin P, Jung S, Johnson J, et al. CALGB 50803(ALLIANCE): a phase 2 trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 063.

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56. Dreyling M, Gordon L, Rule S, et al. A phase 3 study of ibrutinib in combination with

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57. O’Connor OA, Pro B, Illidge T, et al. ECHELON-2: phase 3 trial of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients (pts) with CD30+ mature T-cell lymphomas (MTCL). Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 138.

58. Viviani S, Zinzani PL, Rambaldi A, et al. ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203-212.

59. Mounier N, Brice P, Bologna S, et al. ABVD (eight cycles) versus BEACOPP (4 escalated cycles to 4 baseline) in stages III-IV low risk Hodgkin lymphoma (IPS 0–2): final results of LYSA H34 trial. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 127.

60. Radford J, Younes A, Pro B, et al. Progression-free survival analyses of two pivotal phase 2 studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma or systemic anaplastic large-cell lymphoma. Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 303.

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Genomic Sequencing Assay Potentially a Game Changer Caroline Helwick

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ollywood, FL – Genomic profiling of individual tumors represents a paradigm shift in oncology and holds great promise for patients, according to Gary Palmer, MD, JD, MBA, MPH, Senior Vice President, Medical Affairs and Commercial Development, Foundation Medicine, who described this new genomic Gary Palmer, MD, assay at the Third Annual Conference of the Association for Value-Based Cancer Care.

JD, MBA, MPH Before his position with Foundation Medicine, Dr Palmer led the development of the Oncotype DX® Breast Cancer Assay for Genomic Health.

In recent years, Foundation Medicine has sequenced hundreds of breast cancer tumors. “I looked at the first

50. No two genomic reports were identical,” he noted.

“There are 50 different genomic patterns in those breast cancers, which gives you an idea of the precision that we are dealing with.”

Why the Current Testing Model Is Not Sustainable Under the new paradigm, cancer is no longer described by its tumor of origin, but by its molecular characteristics – and increasingly by its genetic mutations.

Given the increasing number of mutations identified per tumor, the current method of genetic testing is not comprehensive enough, according to Dr Palmer.

Most oncologists now order specific panels. The lung cancer panel, for example, tests for abnormalities in EGFR, KRAS, ALK, and ROS1. “The problem is that the number of impor­ Focused Sequencing of the Clinically Relevant Cancer Genes May Be the tant alterations is increasing, and you Table

Optimal Approach to Patient Care won’t be able to send little pieces of tissue for 20 individual tests,” he exMean identified genomic alterations, N plained. “Also, there is no reason to Foundation think that these 4 alterations represent Cancer type Whole genome Whole exome Medicine all we need to know about lung cancer.

We would miss all the other potential Lung 38,400 528 3.1 adenocarcinoma1 alterations if we just tested for those.

The current model isn’t sustainable.”

Squamous-cell lung 25,900 365 3.2 Whole-genome sequencing has 2 cancer identified a mean number of 15,300 Colorectal cancer3 10,240 140 2.9 genomic alterations per patient (Table), but the vast majority are pasGlioblastoma 7360 101 2.9 senger mutations whose clinical relemultiforme4 vance is unknown; the current method 5 Ovarian cancer 6700 92 2.9 is also likely to miss several actionable alterations in individual patients, Breast cancer6 3200 44 3 many of which are proving to be unTotal 15,300 212 3 predictable. For example, Foundation Whole genome/exome sequencing identifies high numbers of alterations per Medicine research has shown that patient, but the vast majority are passenger mutations whose clinical relevance HER2 amplifications and mutations is unknown. Uneven coverage generated by current whole/exome sequencing occur in many solid tumors, not just increases the probability of missing actionable alterations in an individual breast and gastric, and that many papatient. tients with such tumors have respond1. Imielinski M, et al. Cell. 2012;150:1107-1120. ed to anti-HER2 agents.

2. Cancer Genome Atlas Research Network. Nature. 2012;489:519-525.

3. Cancer Genome Atlas Research Network. Nature. 2012;487:330-337.

4. Cancer Genome Atlas Research Network. Nature. 2011;474:609-615.

5. Cancer Genome Atlas Research Network. Nature. 2008;455:1061-1068.

6. Banerji S, et al. Nature. 2012;486:405-409.

Courtesy of Foundation Medicine.

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FoundationOne Test: A Paradigm Shift The FoundationOne pan-cancer, next-generation sequencing assay

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identifies actionable alterations in tumors that usually would not have been Figure 1 Sample Report I identified by the panel type of approach that is currently being used. The test, which runs on paraffin-embedded tisPatient and ordering physician information sue, hunts for the presence of 236 genes known to be cancer drivers. Although the assay identifies on average 1800 alSummary of results terations per tumor, approximately 10 and genomic are deemed important. The test, therealterations identified fore, weeds out approximately 1790 useless genes per sample, primarily sinTargeted therapies gle nucleotide polymorphisms and pasand clinical trials senger mutations. that may be relevant In 23% of the tumors, however, no based on genomic alterations identified actionable alteration is found. Of this 23%, an alteration can be identified in 14% of tumors, but a targeted treatClear results presented on the first page ment is currently lacking; for the other 9%, no alteration is identified.

“We separate the wheat from the chaff, and we come up with driver al- Figure 2 Sample Report II terations that we report to the oncologist,” Dr Palmer said. “Most impor­ An interpretive The therapies section statement provided provides details on tant, we report the data in a way that for each genomic approved therapies makes sense to the physician and that alteration, including to which the patient’s supports the use of a particular targetthe frequency of cancer may be alteration (COSMIC), sensitive or resised therapy. Focused sequencing of the its biological implicatant based on their clinically relevant genes may be the tion, and what it may genomic profile optimal approach for patient care,” Dr mean for the specific patient Palmer suggested (Figures 1 and 2).

Page 1 of the report lists the alterations and the potential actions – that The clinical trials The appendix lists all section provides reference information is, the use of a US Food and Drug Addetail on currently for studies used in ministration (FDA)-approved drug on available clinical trials curating the report label or off label, or the use of a clinical for which the patient may be eligible trial. Additional pages of the report provide background and content.

Hundreds of physicians have been using the FoundationOne test for the common solid tumors, and for rare tuAdditional pages provide background and context mors, for which treatments are lacking.

“There is no tumor type yet where I would say that we don’t stand much chance of finding anything of value,” Dr Palmer added. a registry has been initiated. Because randomized conA summary of findings and treatment outcomes from the trolled trials will never be conducted on these very first 2223 patients are expected to be reported at the small genetic subsets, the aggregation of rare mutations 2013 annual meeting of the American Society of Clinican generate a database that will be very informative cal Oncology. for oncologists whose patients fit these rare profiles.

“We are heavily invested in getting this information Future Goals and Cost Implications and allowing physicians to use it,” Dr Palmer said.

The next step is to optimize the reporting of treatThe availability of molecular testing on this scale ments that are employed and their outcomes, for which leads to the question of which patients should have these

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tests, because there will be cost implications, he noted.

In one scenario, the test is ordered after patients have exhausted their current treatment options. In the other scenario, the test is used after a metastatic diagnosis, which could spare patients futile chemotherapy. “The economic implications would be different,” Dr Palmer pointed out.

The test also raises the question of off-label drug accessibility in the absence of randomized trials. “It’s one thing to find a target, and another to get the drug off label from the insurance company,” he added.

Sample Patient Using FoundationOne Test Dr Palmer described several good outcomes that have resulted from the FoundationOne test. One patient was a 43-year-old never-smoker who developed lung cancer.

The Vysis ALK Break Apart FISH Probe Kit, an approved companion diagnostic for the anaplastic lympho-

ma kinase (ALK) mutation, was negative. Testing for the epidermal growth factor receptor by polymerase chain reaction was also negative. The patient was started on chemotherapy, but this was ineffective. His physician contacted Foundation Medicine based on the clinical suspicion of a treatable oncogenic driver mutation.

The test identified an ALK rearrangement involving intron 19. Unlike the echinoderm microtubule-associated protein-like 4-ALK rearrangement, which occurs in approximately 5% of patients with non–small-cell lung cancer, this particular mutation has not been reported in the literature. The patient was started on crizotinib, to which he continues to respond at 9 months.

“This would not be found by conventional testing, which seeks only molecular information associated with cancer in a specific organ,” Dr Palmer noted. “The molecular information led to treatment with an FDA-approved agent.” u

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SCIENTIFIC CONFERENCES 2013-2014:

AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Co-Chairpersons: Jeffrey A. Engelman, Lee J. Helman, and Sabine Tejpar October 19-23, 2013 • Boston, MA Twelfth Annual International Conference on Frontiers in Cancer Prevention Research Chairperson: Paul J. Limburg October 27-30, 2013 • National Harbor, MD Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes Co-Chairpersons: John M. Maris, Stella M. Davies, James R. Downing, Lee J. Helman, and Michael B. Kastan November 3-6, 2013 • San Diego, CA The Translational Impact of Model Organisms in Cancer Co-Chairpersons: Cory Abate-Shen, A. Thomas Look, and Terry A. Van Dyke November 5-8, 2013 • San Diego, CA Ninth Annual Personalized Medicine Conference Chairperson: Raju Kucherlapati November 6-7, 2013 • Boston, MA Advance registration deadline: Friday, October 11 Sixth AACR Conference on The Science of Cancer Health Disparitites in Racial/Ethnic Minorities and the Medically Underserved Co-Chairpersons: John D. Carpten, Christopher I. Li, and Olufunmilayo I. Olopade December 6-9, 2013 • Atlanta, GA Advance registration deadline: Thursday, October 24 CTRC-AACR San Antonio Breast Cancer Symposium Co-Directors: Carlos L. Arteaga, C. Kent Osborne, and Peter M. Ravdin December 10-14, 2013 • San Antonio, TX Early registration deadline: Thursday, October 31

AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer Co-Chairpersons: Roy Herbst, Elisabeth Brambilla, Pasi Jänne, and William Pao January 6-9, 2014 • San Diego, CA Abstract submission and award application deadline: Monday, October 14 Advance registration deadline: Tuesday, November 26 AACR-Prostate Cancer Foundation Conference on Advances in Prostate Cancer Research Co-Chairpersons: Arul M. Chinnaiyan, William G. Nelson, June M. Chan, and Jonathan W. Simons January 18-21, 2014 • San Diego, CA Cancer Susceptibility and Cancer Susceptibility Syndromes Co-Chairpersons: Alan D. D’Andrea, Phillip A. Dennis, and Pier Paolo Pandolfi January 29-February 1, 2014 • San Diego, CA Abstract submission deadline: Wednesday, November 13 Advance registration deadline: Monday, December 9 RAS Oncogenes: From Biology to Therapy Co-Chairpersons: Frank McCormick, Dafna Bar-Sagi, and Channing J. Der February 24-27, 2014 • Lake Buena Vista, FL Abstract submission and award application deadline: Friday, December 6 Advance registration deadline: Monday, January 13 Cellular Heterogeneity in the Tumor Microenvironment Co-Chairpersons: Mary Helen Barcellos-Hoff, Michele De Palma, and M. Celeste Simon February 26-March 1, 2014 • San Diego, CA Abstract submission and award application deadline: Monday, December 16 Advance registration deadline: Monday, January 13 AACR Annual Meeting 2014 Chairperson: Scott W. Lowe April 5-9, 2014 • San Diego, CA

AVBCC ANNUAL CONFERENCE

Pathways Creating More and More Value Caroline Helwick

Hollywood, FL – Pathways continue to be refined toward value-based care, adapting to the challenges of a rapidly shifting oncology landscape, as 2 speakers at the Third Annual Conference of the Association for Value-Based Cancer Care described.

Michael A. Kolodziej, MD, National Medical Director for Oncology Strategies at Aetna, Hartford, CT, and Marcus A. Neubauer, MD, Medical Director, Oncology Services, US Oncology/McKesson Specialty Health, TX, first discussed market pressures and the need to control costs.

Since 1996, the US gross domestic product has decreased by 2.4%, but healthcare costs have risen by 9.2%, and the cost of cancer medical care, as well as oncolytics, has increased by 15%. The fiscal future looks even bleaker, with cancer care costs projected to rise 39% by 2020. The consequence of this financial crisis is confusion by these market forces, Dr Neubauer suggested. “All stakeholders are struggling. Payers are struggling with rising costs and have problems getting their programs adopted by physicians. Physicians often have multiple platforms to manage. Employers are struggling with costs” (Figure 1).

In response, oncology management solutions are continuing to evolve, but this is creating a fragmented approach to quality. “We are not doing a great job solving this problem,” Dr Neubauer said.

Dr Kolodziej said that pathways are a way to carry out Aetna’s principles: to drive the efficient use of evi-

dence-based medicine, to avoid waste and the misuse of medical services, and to leverage and integrate the many current and future medical and pharmacy cancer care initiatives.

As responsibility, risk, and accountability shift to the provider, pathways will become ever more impor­ tant for communicating and measuring performance, Dr Kolodziej added. “They prove you are accomplishing minimal standards, but most important, they train oncologists to get in the mindset of measurements and process improvements. They are training sets for changing behavior.”

Demonstrating Cost Savings US Oncology/McKesson has responded by creating value-based pathways, believing that pathways can save money, without diminishing outcomes. Despite the size of the network – which includes more than 3000 oncologists, 2200 multispecialty practices, and 1.5 million patients with cancer annually – the pathways program is “very internal,” Dr Neubauer said.

“In our physician-driven program, all our pathways are designed by oncologists, with the intent of showing that we can achieve both value and a value-based contract with payers. We have had some success in this regard,” he noted.

Two recent studies provided proof of principle of this. Dr Neubauer led a study of patients with non– small-cell lung cancer that showed that on-pathway treatment saved almost $10,000 – a 35% reduction – versus off-pathFigure 1 The Consequences: Market Forces Are Creating Confusion way treatment (Neubauer MA, et al. J Oncol Pract. 2010;6:12-18).

Hoverman and colleagues (also Payers Employers with US Oncology) reached the • Limited consistency between • Confusing definition of quality and same conclusions in their study of payers coverage • Challenges getting provider • Little ability to weigh cost versus patients with colon cancer, where adoption quality on-pathway treatment saved • Beginning to focus on prior • Need a trusted source for under$50,000 to $60,000 per case, more authorization to gain adoption standing quality than a 30% reduction versus off-pathway treatment (Hoverman Providers Patients/Employees JR, et al. J Oncol Pract. 2011;7 [3 • Multiple platforms and policies to • Confusing messages on quality care Suppl]:52S-59S). manage • “Best” option not always available Combining value-based path• Inconsistent yardsticks for quality • Limited ability to compare ways with additional services, such resulting in variability in care for • Fear and frustration similar patients as advanced care planning and patient support services, resulted in a

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12% cost savings within the US Oncology Network, Dr Neubauer added.

Dr Kolodziej presented additional data on savings from 2 pilot studies, demonstrating that emergency department use and inpatient days steadily declined when pathways were implemented. “Both pilots are showing equal, if not better, clinical outcomes and patient satisfaction,” he said.

Figure 2 NCCN, the US Oncology Network, and McKesson Each Brings Complementary Strengths to Create New Solutions: Emphasis on Comprehensive Quality NCCN • Academic thought leadership • World-class content

McKesson • Community care operational excellence

• Strong payer and employer relationships

• Leading technology • Expansive provider relationships

• Recognized name brand

• Resources of a Fortune 14 company

• Emphasis on value and Value-Based Pathways quality To further strive for value within a pathway system, US Oncology/Mc­ Bringing content and technology from 2 organizations closer together Kesson has partnered with the Nacreates new opportunities and enhances individual strengths tional Comprehensive Cancer Network (NCCN), capitalizing on the individual strengths of each entity (Figure 2). will pathways be designed for tumors that are defined The Value Pathways are based on the NCCN Clinimore by molecular biology than by site of disease? cal Practice Guidelines in Oncology – the gold standard for evidence-based oncology content – paired with quanDiscussion With the Experts tified pharmacoeconomics, thus creating “Value PathDr Neubauer and Dr Kolodziej responded to quesways that are powered by the NCCN,” Dr Kolodziej said. tions from the Association for Value-Based Cancer “With this collaborative vision, we hope to create Care conference audience. meaningful content and a technology standard,” he commented. “We can be universally recognized for driving quality patient care; we can provide increased “With this collaborative value transparency for providers, payers, and employvision, we hope to create ers; and our content can be integrated with physician meaningful content and a work flow to enable programs across all providers and payers.” technology standard…[and] Value Pathways will be administered via the NCCN’s we can provide increased value new technology standard, Clear Value Plus, which is a program that integrates with patient workflow; imports transparency for providers, patient and clinical data from frequently used electronpayers, and employers.” ic health records; identifies relevant Value Pathways and NCCN guidelines at the point of care; and allows —Michael A. Kolodziej, MD providers, payers, and employers to align on quality and value.

“Clear Value Plus’s advanced, real-time reporting Q: Can pathways affect the need for prior authorizaprovides aggregate, actionable data for providers and tion for new drugs? payers,” Dr Kolodziej added. “Our primary customer is Dr Neubauer: Obviously, pathways must be relethe physician, but we are showing this tool to payers vant, and therefore must be able to incorporate new too. We hope that physicians will be able to use this as drugs quickly. But they must be evidence based, and we their standard rather than having to participate in a must consider all factors. If we don’t think a new drug number of different programs.” is worthy, we won’t necessarily put it onto our pathway, Pathways must be adapted to changes occurring even if it passes muster by the US Food and Drug Adacross the oncology landscape, he added, but there reministration. If the drug is expensive and produces good main unanswered questions: With the growing availresults, yes. ability of generic drugs, how will the “economic value Dr Kolodziej: When I joined Aetna a few months proposition” be defined in a world with generic alternaago, one of the first things I did was review our oncolotives for which there is not much differentiation? How gy drug prior authorizations. We only require prior au-

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thorizations for 2 injectables, Xgeva and Aloxi. We don’t set that bar very high, but we do for orals, largely driven by their price tags. The beauty of pathways is that they eliminate administrative responsibilities that plans have to worry about, and they lessen the need for so many prior authorizations.

Dr Neubauer: But, payers do have to step in, in some way, although prior authorization is not a longterm proposition for anyone. We must develop a way to collaborate.

“In our physician-driven program, all our pathways are designed by oncologists, with the intent of showing that we can achieve both value and a value-based contract with payers. We have had some success in this regard.” ­—Marcus A. Neubauer, MD Q: The elephant in the room is the cost of the drugs themselves. Is the cost structure appropriate, and how can drug costs be controlled?

Dr Kolodziej: There are proposals on the table. The government may have to step in. Bundled reimbursements may have some influence, although I am skeptical. Great Britain has started value-based reimburse-

ments, in which companies will be reimbursed only for the first 2 cycles if their drug does not seem effective.

As we set up integrated delivery systems, pharmaceutical companies may want to come to those systems with value-based propositions, perhaps based on outcomes, and negotiate a price point over the drug’s potential value. That’s a pie-in-the-sky deal, but we have been engaged in discussions about this as an engine to drive the correct pricing of drugs. Of course, nobody wants to take that beast on. It’s a political minefield.

Dr Neubauer: I don’t understand how the government can reduce the bill for chemotherapy from average sale price (ASP) plus 6% to ASP plus 4%, but leave the ASP part – which the pharmaceutical company gets – unchanged. My opinion is that the government will start regulating prices as other countries do, or pharmaceutical companies will have to step up to the table. Pharmaceutical companies are starting to talk about value propositions, but these are early conversations and may not materialize.

Q: How useful are patient registries in producing meaningful data?

Dr Kolodziej: I take exception to the argument that we should have provider- or community-based registries to give us information about real-world experience.

That’s not to say we cannot learn something from what functionally is comparative effectiveness research.

Dr Neubauer: Registries could be valuable, and there are efforts under way to develop them, such as American Society of Clinical Oncology’s CancerLinQ. But based on my efforts to try to analyze our own data, I can say it’s very difficult. u

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RENAL CELL CARCINOMA

Genetic Susceptibility to Renal Cell Carcinoma Cristi Radford, MS, CGC

I

n 2013, approximately 65,000 people will be diagnosed with kidney cancer and twothirds will be men.1 The term kidney cancer generally refers to any cancer arising in the kidney or renal pelvis. However, this article will focus on the most common type of kidney cancer seen in adults, renal cell carcinoma (RCC).1 RCC arises from cells in the tubules of Cristi Radford, the filtration portion of the kidney. There are MS, CGC several histologic subtypes. Clear cell is the most common form (75%-80%), followed by papillary types 1 and 2 (10%-15%), chromophobe (5%), and collecting duct (<1%).1-5 Each subtype possesses unique clinical characteristics, genetic alterations, and responses to therapy.

Genetic diagnosis is imperative in helping to obtain surveillance for at-risk family members and developing tailored medical management for the patient.

Similar to other types of cancer, the majority of RCC cases are sporadic. Sporadic RCC typically pre­ sents as a solitary lesion and is diagnosed in the sixth decade of life and beyond.5,6 Hereditary RCC, on the other hand, typically develops earlier in life and often involves bilateral, multifocal tumors.4 Unlike sporadic RCC, which is more common in men, the gender dis-

KEY POINTS Typically, hereditary renal cancer presents at an earlier age and is often multifocal and/or bilateral.

Most syndromes are characterized by a particular histologic subtype of renal cancer and other associated features. ➤ Genetic diagnosis can help obtain surveillance for at-risk family members. Additionally, with the exception of HLRCC, surgical management tries to focus on nephron-sparing surgery. ➤ Pathology can be useful in diagnosing hereditary RCC. However, as it is believed most hereditary RCC cases remain undiagnosed, it is likely we may see expanded phenotyping in the future. ➤

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tribution in hereditary forms tends to be equal7 or have a greater female preponderance.8 The most well-recognized RCC syndromes are von Hippel-Lindau (VHL), hereditary leiomyomatosis and renal cell carcinoma (HLRCC), Birt-Hogg-Dubé (BHD), and hereditary papillary renal carcinoma (HPRC). Approximately 4% of all RCC cases are due to an inherited susceptibility.6 As RCC continues to be associated with additional genes, however, and because it is believed that the majority of hereditary RCC cases go unrecognized, it is likely that this is an underestimate.6 With the exception of HPRC, each syndrome is associated with its own, unique extrarenal manifestations. In some syndromes, extrarenal manifestations are the most common, and RCC develops only in a small subset. There are 2 primary goals for medical management of RCC: prevention of metastatic disease and preservation of renal function.6 Some suggest a surveillance protocol for VHL, HPRC, and BHD, which observes the patient with serial imaging until the largest renal lesion becomes 3 cm in size, at which time surgical intervention in the form of nephron-sparing surgery is warranted.9 At present, preventive screening measures for RCC are applied only in people with an increased risk of developing the condition. Thus, genetic diagnosis is imperative in helping to obtain surveillance for at-risk family members and developing tailored medical management for the patient with RCC. A summary of VHL, HLRCC, BHD, and HPRC follows. Genetic counseling and possibly genetic testing should be included in patients with a personal or family history of any of the following: • Bilateral and/or multifocal RCC • RCC under age 50 years • RCC and another primary cancer in the same individual • RCC and a family history of cancer • RCC and nonrenal manifestations associated with hereditary RCC (in patient and/or family members), such as hemangioblastomas, pheochromocytomas, cutaneous leiomyomas, fibrofolliculomas, and pneumothorax

VHL Syndrome Of the 4 syndromes – VHL, HLRCC, BHD, and HPRC – VHL is the most recognized and described. It is an autosomal-dominant, multisystem condition linked

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to mutations in the VHL gene. Penetrance is high, approaching 90% to 100%, and expressivity varies greatly.

Manifestations include kidney, adrenal, pancreatic, reproductive adnexal organs, and central nervous system (CNS) lesions.

Renal findings include both cysts and RCC. Of those with VHL syndrome, the lifetime risk of developing RCC is 25% to 45%, almost always clear cell.2 Individuals may develop 600 tumors and 1100 cysts per kidney.3,9 The average age at onset of renal manifestations is 39 years.2 Approximately 10% to 20% of individuals will have adrenal findings in the form of pheochromocytomas, either in one or both glands.10 Pancreatic findings consist of both pancreatic cancer and cysts, which may be numerous but are usually simple cysts.

Up to 17% of individuals with VHL may develop neuroendocrine tumors of the pancreas.11 Men often have epididymal tumors, which typically do not cause problems; in women, papillary cystadenoma of the broad ligament may be seen, although rarely.11 CNS involvement is high, with the majority of patients having hemangioblastomas (60%-80%) and some developing endolymphatic sac tumors (10%-15%).10 CNS hemangioblastoma is the cardinal feature of VHL, the majority found in the brain (80%), followed by the spinal cord (20%).10 Retinal hemangioblastomas, sometimes called retinal angiomas, are often the initial manifestation of VHL, affecting up to 70% of individuals; the average age at diagnosis is 25 years, but they may present in childhood.11 Approximately 10% of individuals with VHL develop endolymphatic sac tumors, which result in varying severities of deafness; these are often misdiagnosed as MÊnières disease and may be an initial presenting feature of VHL.11

authors suggest surveillance even in childhood.12 The associated renal cancer, papillary type 1, is also more aggressive and more prone to metastasis than with other RCC syndromes. Early radical treatment by nephrectomy has been proposed due to the aggressive natures of these tumors. It has also been suggested that renal cancer surveillance be restricted to families with previous cases of renal cancer or specific FH mutations, but there is no evidence that family history or type of FH mutation can predict renal cancer risk. Therefore, current data indicate that surveillance should be aimed at all carriers of the FH mutation. Collecting-duct RCC and mixed cystic, papillary, and tubulopapillary RCC have also been reported in HLRCC families.2 In addition to RCC, individuals with HLRCC are at risk of developing cutaneous and uterine leiomyomas.

Cutaneous leiomyomas are typically distributed on the head, neck, trunk, and extremities. The majority of

HLRCC Syndrome HLRCC is unique among other hereditary RCC syndromes in that most kidney tumors seen in HLRCC are unifocal and unilateral.12 Similar to the other RCC syndromes, HLRCC is inherited in an autosomal-dominant fashion. The syndrome was initially reported in 200113 and is associated with mutations in the FH gene.

The number of families who develop renal cancer varies widely in the literature; therefore, a specific renal cancer risk for carriers of the FH mutation has not yet been determined. The incidence in families is believed to range from 10% to 40%.2,14 Age of onset is also challenging; patients are diagnosed between the ages of 30 and 45, but on occasion, onset occurs prior to age 20.12 Surveillance recommendations for these families also vary, but intensive screening for renal cancer is usually suggested beginning at age 18 or 20, and due to reports of childhood onset, the youngest being age 11, some

BHD Syndrome Similar to HLRCC, BHD has been associated with renal tumors and cutaneous manifestations. Additionally, BHD is associated with pulmonary cysts and spontaneous pneumothoraces. Inheritance is also autosomal dominant, and the syndrome is linked to mutations in the FLCN gene. Similar to VHL and HPRC, renal tumors tend to be bilateral and multifocal. Kidney tumor types are more diverse than in the other RCC syndromes and include oncocytic hybrid tumor (67%), chromophobe RCC (23%), and renal oncocytoma (3%); clear cell RCC and papillary renal carcinoma have also been reported. The average age at diagnosis is 48 years.15 Similar to other syndromes, a specific renal cancer risk has not yet been definitely determined; however, the prevalence of kidney tumors in families ranges from 6.5% to 34%.15 As the associated tumors tend to be slow growing, bilateral, and multifocal, the

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Retinal hemangioblastomas are often the initial manifestation of VHL, affecting up to 70% of individuals. individuals (76%) will present with 1 or more cutaneous leiomyomas, with mean age of presentation being 25 years.14 Uterine leiomyomas are present in all females with HLRCC and are distinct from those found in the general population in that the age of onset is younger (often under age 30) and the fibroids are numerous and larger; myomectomy or hysterectomy is sometimes required.14

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use of nephron-sparing surgery to preserve functioning renal tissue is recommended.

Numerous cutaneous findings are associated with BHD and include fibrofolliculomas, trichodiscomas, acrochordons, perifollicular fibromas, and angiofibromas.15 The follicular tumors are typically distributed over the face, neck, and upper trunk.15,16 As fibrofolliculomas are the only skin finding specific for BHD, a dermatologic diagnosis can be made when 5 or more facial or truncal papules are present with at least one being a histologically confirmed fibrofolliculoma.15 The average age of onset is in the third and fourth decades of life.15 In addition to being at increased risk for renal neoplasms and cutaneous findings, individuals are also at risk for pulmonary disease consisting of multiple lung cysts and spontaneous pneumothoraces.16 Almost 90% of individuals have multiple, bilateral lung cysts, which are typically asymptomatic, and 24% of individuals have a history of pneumothorax.15

HPRC Syndrome Unlike the other syndromes, the sole manifestation of HPRC is type 1 papillary renal carcinoma. However, it is important to keep in mind that type 1 and type 2 papillary renal carcinomas are often not distinguished in the initial pathology. This syndrome is also inherited in an autosomal-dominant fashion with variable penetrance and is associated with mutations in the MET gene. Similar to VHL and BHD, individuals are at risk of developing multiple and/or bilateral tumors. The risk is greatest in the sixth through eighth decades.2,6 Other Syndromes It is important to realize that VHL, HLRCC, BHD, and HPRC are not the only inherited syndromes associated with RCC; other syndromes reported in the litera-

ture include Cowden syndrome, hereditary paraganglioma and pheochromocytomas associated with SDHB mutations, tuberous sclerosis, Li-Fraumeni syndrome, and Lynch syndrome.17 u

References

1. American Cancer Society. Kidney Cancer (Adult)—Renal Cell Carcinoma. Atlanta, GA: American Cancer Society; 2012. http://www.cancer.org/acs/groups/cid/ documents/webcontent/003107-pdf.pdf. Revised January 18, 2013. Accessed May 13, 2013.

2. Chan-Smutko G. Genetic testing by cancer site: urinary tract. Cancer J. 2012;18(4):343-349.

3. Linehan WM, Pinto PA, Srinivasan R, et al. Identification of the genes for kidney cancer: opportunity for disease-specific targeted therapeutics. Clin Cancer Res. 2007;13(2 pt 2):671s-679s.

4. Lipworth L, Tarone RE, Lund L, et al. Epidemiologic characteristics and risk factors for renal cell cancer. Clin Epidemiol. 2009;1:33-43.

5. Rosner I, Bratslavsky G, Pinto PA, Linehan WM. The clinical implications of the genetics of renal cell carcinoma. Urol Oncol. 2009;27(2):131-136.

6. Barrisford GW, Singer EA, Rosner IL, et al. Familial renal cancer: molecular genetics and surgical management. Int J Surg Oncol. 2011;2011:658767.

7. Azeem K, Kollarova H, Horakova D, et al. Genetic syndromes associated with renal cell carcinoma: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011;155(3):231-238.

8. Mester JL, Zhou M, Prescott N, et al. Papillary renal cell carcinoma is associated with PTEN hamartoma syndrome. Urology. 2012;79(5):1187.e1-7.

9. Singer EA, Bratslavsky G, Middelton L, et al. Impact of genetics on the diagnosis and treatment of renal cancer. Curr Urol Rep. 2011;12(1):47-55.

10. Wind JJ, Lonser RR. Management of von Hippel-Lindau disease-associated CNS lesions. Expert Rev Neurother. 2011;11(10):1433-1441.

11. Frantzen C, Links TP, Giles RH. Von Hippel-Lindau disease. In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 2000. http://www.ncbi.nlm.nih.gov/books/NBK1463/. Updated June 21, 2012. Accessed May 13, 2013.

12. van Spaendonck-Zwarts KY, Badeloe S, Oosting SF, et al. Hereditary leiomyomatosis and renal cell cancer presenting as metastatic kidney cancer at 18 years of age: implications for surveillance. Fam Cancer. 2012;11(1):123-129.

13. Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A. 2001;98(6):3387-3392.

14. Pithukpakorn M, Toro JR. Hereditary leiomyomatosis and renal cell cancer. In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 2006. http://www.ncbi.nlm.nih.gov/books/NBK1252/. Updated November 2, 2010. Accessed May 13, 2013.

15. Toro JR. Birt-Hogg-Dubé syndrome. In: Pagon RA, Bird TD, Dolan CR, et al.

GeneReviews. Seattle, WA: University of Washington, Seattle; 2006. http://www. ncbi.nlm.nih.gov/books/NBK1522/. Updated September 9, 2008. Accessed May 13, 2013.

16. Tefekli A, Akkaya AD, Peker K, et al. Staged, open, no-ischemia nephron-sparing surgery for bilateral-multiple kidney tumors in a patient with Birt-Hogg-Dubé syndrome. Case Rep Med. 2012;2012:639629.

17. Lodish MB, Stratakis CA. Rare and unusual endrocrine cancer syndromes with mutated genes. Semin Oncol. 2010;37(6):680-690.

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SECOND ANNUAL CONFERENCE

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November 6-7, 2013 • Joseph B. Martin Conference Center at Harvard Medical School • Boston, MA.

How do you help people realize the potential of personalized medicine?

Join more than 600 national and international thought leaders as speakers, panelists, and attendees who will be a part of the discussions about the status and future of personalized medicine as a healthcare paradigm.

Keynote addresses include: • Personalized Medicine; For Changing Tomorrow, Yoshihiko Hatanaka, • • • • • •

Astellas Pharma, Inc. Accelerating Medical Solutions, Michael Milken, M.B.A., The Milken Institute; FasterCures FDA Program in Drug Development and Companion Diagnostics of How the FDA Promotes Personalized Medicine, Elizabeth Mansfield, Ph.D., FDA Plans for Implementing Personalized Medicine in Canada, Pierre Meulien, Genome Canada PhRMA’s Outlook on Personalized Medicine, William Chin, M.D., PhRMA CMS Beneficiaries and the Role of Personalized Medicine in Improving American Healthcare, Patrick Conway, M.D., MSc, Centers for Medicare & Medicaid Services; Center for Clinical Standards & Quality Novel Solutions - Crowdsourcing: A New Approach for Innovation in Personalized Medicine, Karim R. Lakhani, Ph.D., M.S., Harvard Business School; Harvard-NASA Tournament Lab at the Institute for Quantitative Social Science

Also included: • Panel discussions, Harvard Business School Case Study, and the Personalized Medicine Coalition’s Ninth Annual Award for Leadership in Personalized Medicine CONFERENCE CHAIRPERSON: Raju Kucherlapati, Ph.D., Paul C. Cabot Professor of Genetics, Professor of Medicine, Harvard Medical School

For more information and to register for this important event, go to www.aacr.org/PM.

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2013 ASCO ANNUAL MEETING

Ponatinib Given Early May Stem Resistance in CML Alice Goodman

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utation analysis at baseline and at the end of treatment (EOT) provides information about the response to ponatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphocytic leukemia (ALL) enrolled in the phase 2 PACE study. Results were presented at the 2013 AnMichael WN Deininger nual Meeting of ASCO. Ponatinib is an oral pan-BCR-ABL1 tyrosine kinase inhibitor (TKI) with potent activity against native and mutated BCR-ABL1 and other kinases. The drug has demonstrated activity against all clinically relevant mutations associated with resistance to TKI therapy in vitro, including the T315I mutation. Ponatinib is the first TKI in phase 2 studies that is active against the T315I mutation.

Ponatinib has demonstrated activity against all clinically relevant mutations associated with resistance to TKI therapy in vitro.

The study included patients with CML or Ph+ ALL resistant or intolerant to dasatinib or nilotinib (n=203) or with a confirmed T315I mutation at baseline (n=64).

Patients were heavily pretreated, with 93% having received 2 or more prior TKIs and 58% having received 3 or more prior TKIs. “We observed that the overall rate of mutations increases with stage, and so does the number of mutations for each individual,” noted lead author Michael W. N. Deininger, MD, PhD, University of Utah’s Huntsman Cancer Institute, Salt Lake City.

When ponatinib was given at therapeutic doses, no single mutation was found to confer resistance to ponatinib during the study. In studies of other TKIs in CML, the T315I mutation is typically associated with resistance.

Responses to ponatinib were observed regardless of

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mutation status or disease stage (ie, chronic, accelerated, or blast phase/Ph+ ALL). Durable responses to ponatinib were observed in chronic phase CML, with 91% achieving a major cytogenetic response (MCyR) that persisted at 12 months (MCyR was the primary end point for chronic phase patients, and major hematologic response was used for accelerated and blast crisis phases).

Chronic phase patients with T315I mutations tend to do very well, but those with no single demonstrable mutation do slightly worse, with only 25% MCyR in chronic phase, Deininger noted.

Overall results of the study were reported separately according to disease stage. In chronic phase CML, few patients who discontinued treatment with ponatinib gained single mutations at EOT, and many patients who did gain mutations had been treated with ponatinib at low-dose intensity. Few of these patients developed compound mutations, and there was no change in mutation status for the majority of patients at EOT. In the accelerated phase, the majority of patients – approximately 80% – had no change in mutation status at EOT. The situation in blast crisis CML was different.

Slightly more than 50% of patients who discontinued treatment with ponatinib developed multiple or compound mutations, but still there was no change in mutation status for a significant proportion of patients.

“These findings suggest that mechanisms other than compound mutations are responsible for resistance to ponatinib in patients in blast crisis,” Deininger told listeners.

“If we introduce ponatinib early in the course of therapy, this drug may be able to suppress the emergence of single BCR-ABL1 mutations, and as a result, the development of compound mutations,” he stated. u

Reference

Deininger MWN, Cortes JE, Kim D-W, et al. Impact of baseline mutations on response to ponatinib and end of treatment mutation analysis in patients with chronic myeloid leukemia. J Clin Oncol. 2013;31(suppl):Abstract 7001.

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Olaparib Maintenance Therapy Slows Progression in Patients With Ovarian Cancer and BRCA Mutations Alice Goodman

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laparib maintenance therapy prolonged progression-free survival (PFS) and the time to disease progression after a second subsequent therapy (PFS2) in patients with platinum-sensitive relapsed serous ovarian cancer (SOC). The effect of olaparib was particularly robust in patients with a BRCA mutation in an updated analysis of Study 19 presented at the 2013 Annual Meeting of ASCO. In patients with a BRCA mutation, the median improvement with olaparib versus placebo was 6.9 months for PFS and 8.5 months for PFS2, both of which were statistically significant. Overall survival (OS) was improved by 3 months compared with placebo, but this difference did not reach statistical significance.

“Olaparib maintenance therapy led to the greatest clinical benefit compared with placebo in patients with a BRCA mutation. As a result of these compelling data, phase 3 confirmatory trials will begin this year in SOC patients with a BRCA mutation,” stated presenting author Jonathan Ledermann, BSc, MD, FRCP, Professor of Medical Oncology in the UCL Cancer Institute, University College London, and an Honorary Consultant Medical Oncologist at UCL Hospitals. Ledermann presented these findings at the 2013 Annual Meeting of ASCO. Study 19 randomized 265 patients with platinumsensitive SOC to either maintenance olaparib 400 mg bid or placebo until disease progression.

The primary results of Study 19 showed that olaparib maintenance therapy significantly extended PFS in SOC patients compared with placebo (P<.00001). OS was not prolonged with olaparib, however (Ledermann J, et al. N Engl J Med. 2012;366:1382-1392).

Updated Analysis of Patients With BRCA Mutations A prespecified subgroup analysis of Study 19 showed that patients with a known BRCA mutation had improved survival on olaparib maintenance compared with placebo.

This observation led to a retrospective analysis of the study to see the effect of olaparib maintenance in patients with BRCA mutations. Using 2 different assays, 136 patients were identified with a germline BRCA mutation or a somatic BRCA mutation, and 118 had wild-type BRCA (a total of 94%).

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In 136 patients with BRCA mutations, a highly significant 82% reduction in risk of progression was observed for ola­parib maintenance therapy (P<.00005). Median PFS was 11.2 months with olaparib versus 4.3 months with placebo.

A significant but less robust advantage was also observed for olaparib in patients with wild-type BRCA (P=.007).

For all patients, no OS difference was observed for olaparib versus placebo, but there was a trend toward improved OS for olaparib in patients with a BRCA mutation. Ledermann said that longer-term follow-up may show a difference in favor of olaparib.

Median PFS2 significantly favored olaparib maintenance therapy in BRCA-mutated patients (P=.0063); median PFS2 was 23.8 months versus 15.3 months, respectively. PFS2 was also 2.4 months longer with olapar­ ib in the wild-type patients.

Olaparib and placebo had similar effects on quality of life in patients with BRCA mutations. Tolerability was similar in mutated and wild-type patients, with low-grade nausea and fatigue as the most commonly reported adverse events.

Formal discussant of this trial, Paul Sabbatini, MD, attending physician at Memorial Sloan-Kettering Cancer Center in New York City, pointed out 2 important issues: the effect of subsequent therapies confounding outcomes in the 2 groups, and the timing of maintenance therapy.

It is difficult to show a survival advantage for maintenance olaparib in patients treated with several subsequent lines of treatment, he continued.

Evidence is accruing to suggest that maintenance therapy is most effective in ovarian cancer when initiated later in the course of disease, and this question is being addressed in clinical trials, he noted.

The take-home point from this study, Sabbatini stated, is that the BRCA mutation is a robust biomarker for the benefit of olaparib and will be included in phase 3 studies going forward. But, he continued, study of PARP inhibitors should not be limited to patients with BRCA mutations, as they show efficacy in other patient populations as well. u

Reference

Ledermann JA, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm). J Clin Oncol. 2013;31(suppl):Abstract 5505.

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Bevacizumab Maintenance Improves Survival in mCRC, but Added Erlotinib Is of No Value Alice Goodman

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evacizumab maintenance therapy following induction with bevacizumab-based chemotherapy significantly increases progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC). However, the addition of erlotinib in the maintenance phase does not increase overall survival (OS) compared with bevaciChristophe Tournigand, MD, zumab alone. KRAS status was not a predictor PhD of benefit from erlotinib in this study. A continuous strategy of induction chemotherapy followed by maintenance with bevacizumab-based therapy achieves a median OS of 25 months.

These results from the phase 3 GERCOR DREAM trial were presented at the 2013 Annual Meeting of ASCO by Christophe Tournigand, MD, PhD, Hôpital Saint-Antoine, Paris, France.

Combining a TKI-inhibiting VEGFR agent with an anti-EGFR agent has synergistic activity, even in a KRAS-mutated model.

The rationale for combining bevacizumab and erlotinib in the GERCOR DREAM trial was based on the following observations: combining a TKI-inhibiting VEGFR agent with an anti-EGFR agent has synergistic activity, even in a KRAS-mutated model. Bevacizumab, a VEGF inhibitor, increases survival in mCRC when combined with oxaliplatin- or irinotecan-based first- or second-line chemotherapy. Cross-talk between the EGFR and VEGF pathways is involved in tumor growth and survival.

The study enrolled 700 patients with mCRC treated with 1 of 3 oxaliplatin- or irinotecan-based regimens:

We’re just a

mFOLFOX7 (leucovorin, oxaliplatin, 5-fluorouracil), XELOX2 (capecitabine, oxaliplatin), or FOLFIRI (leucovorin, 5-fluorouracil, irinotecan); bevacizumab was combined with all 3 regimens. Patients who had no progression of disease following chemotherapy were randomized to maintenance therapy with bevacizumab 7.5 mg/kg every 3 weeks + erlotinib 150 mg/day (n=224) or beva­ cizumab alone at the same dose and regimen (n=228); treatment was continued until disease progression.

Baseline characteristics were similar between the treatment arms; ~27% were aged 70 years or older; ~57% were male; ~9% had previous adjuvant chemotherapy; ~18% were metachronous; and ~60% were performance status 0.

No significant difference in PFS between maintenance treatment arms was observed. Maintenance PFS from randomization was a median of 4.6 months with bevacizumab alone versus 5.9 months with bevacizumab + erlotinib. PFS (from registration in the trial) was 9.3 months versus 10.2 months, respectively. Also, OS was not improved by the addition of erlotinib. OS from registration was 27.9 months versus 28.4 months, respectively.

For the KRAS analysis, wild-type KRAS was found in 111 patients in the bevacizumab maintenance therapy group and in 129 patients in the bevacizumab + erlotinib maintenance group. As in the main analysis of the trial, no significant differences in maintenance treatment arms were observed for PFS and OS in patients with wild-type KRAS and those with mutated KRAS, demonstrating that KRAS does not select for patients who will benefit from erlotinib. u

Reference

Tournigand C, Chibaudel B, Samson B, et al. Maintenance therapy with bevacizu­ mab with or without erlotinib in metastatic colorectal cancer (mCRC) according to KRAS: results of the GERCOR DREAM phase III trial. J Clin Oncol. 2013;31(suppl):Abstract 3515.

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CONQUERING THE CANCER CARE

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FIRST ISSUE IN THE 2013 SERIES

CONQUERING THE CANCER CARE

A 6-part series The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series.

Upcoming topics include:

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D ISSUE ™ IN THE 2013 SE RIES SE C O N D ANN UA L

CONQUERING CANCER CARTHE

Changing the Image of Palliative Care Lillie D. Shockney, RN, BS, MAS

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In this issue, we address paln part 2 of clear understanding of the intent of liative care. our Conque series, the ring the Can palliative care today, with the primary Palliation in cancer care is a topic focus is on mat pain man cer Care Continuum agemen goalt.ofDes ending its identification that commonly makes people (medical wel ic improvements inabilitysolely l as surgical in pite drato overco procedures pharmaceu as tica cancer provideddie for wh theile dying. providers as well as patients) uncom- we still me it effe l agecare desi nts, as have a ctively, fear gned in great pai monly resp ing con Instead, palliative be assofortable. I recently had the opportunity cessful on beh long way to go to be to help ™trol pain, care should ond that n. 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Shoc My and said se that o ent l environ of hospita est thatat the time you are planer initiate tive and thisrequ discussion sociated withthe life-threatening through thesoon pre- t,after that thoughines. They also pro tools a to even men did next edition illness, He an inp and me. whe you all to at r it be on he nd the nt unitto to bring s. This the atiefor mati Lillie sure that tful care be taken mote orrespo a clinic visi D. 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2013 INTERNATIONAL CONFERENCE ON MALIGNANT LYMPHOMA

Genomic Sequencing Uncovers the Genetic Landscape of Primary CNS Lymphoma Will likely lead to new targeted therapies for an incurable malignancy Dalia Buffery, MA, ABD

Lugano, Switzerland – The genomic basis of primary central nervous system lymphoma (PCNSL), a very aggressive and incurable type of lymphoma, has not been understood until now. At the 2013 International Conference on Malignant Lymphoma, a team of researchers from the Mayo Clinic and from the University of Virginia presented its recent findings at a poster session involving the most comprehensive study to date of the genomic landscape of PCNSL. Esteban Braggio, PhD, of the Mayo Clinic in Scottsdale, AZ, and colleagues used a variety of tools, including array-based comprehensive genomic hybridization (aCGH), whole-exome sequenc-

New understanding of the genetic makeup of the disease opens the door to the development of new targeted therapies... and potentially improved outcomes. ing, mate pair whole-genome sequencing, and targeted sequencing, to determine whether PCNSL and systemic diffuse large B-cell lymphoma (DLBCL) are different in their molecular makeup and pathogenesis, and whether there is a CNS-specific genetic signature in PCNSL. The team identified a total of 35 genes with aCGH in the 51 cases of PCNSL that were investigated, and additional molecular sequencing screenings were selected for targeted sequencing in other patients with PCNSL. The large majority of cases – 89% of the patients – had abnormalities of the CDKN2A gene, which can be seen

as a unifying characteristic of this disease. In addition, MYD88 mutations were present in 79% of cases, a high prevalence rate. Other genes that were previously identified in DLBCL included inactivated mutations of TNFAIP3 (16%), PRDM1 (16%), GNA13, TMEM­ 30A, B2M, and CD58 (11% each); activated mutations of CD79B (28%) and CARD11 (19%); and translocations of BCL6 (22%) in patients with PCNSL. By contrast, the following mutations identified in this study (that had not been seen in DLBCL) indicate their unique involvement in PCNSL: 11% of PCNSL cases show biallelic inactivation of TOX and PRKCD and 17% of cases show monoallelic inactivation in these 2 genes. The investigators therefore suggest that TOX, a T-cell development regulator, has a key role in the pathogenesis of PCNSL, based on its high prevalence in abnormalities related to this gene. This study confirms that the genetic signature of PCNSL is associated with post–germinal center DLBCL and is involved in a subset of disease-specific abnormalities. It further shows a large number of genes that are involved in the immune response, lymphocyte differentiation, disease proliferation, and in apoptosis. Furthermore, this new understanding of the genetic makeup of the disease opens the door to the development of new targeted therapies for this type of cancer and potentially improved outcomes. u

Reference

Braggio E, O’Neill B, VanWier S, et al. The genomic landscape of primary central nervous system lymphoma (PCNSL). Presented at: 12th International Conference on Malignant Lymphoma; June 19-22, 2013; Lugano, Switzerland. Abstract 168.

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LETTER

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EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances.

In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting.

to learn more!

Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

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FACULTY Kenneth C. Anderson, MD Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Tina Flaherty, ANP-BC, AOCN Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute Boston, MA

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THE LAST WORD

To PARP or Not to PARP – What Is the Question?

Perspective on the First “Disappointment” With a New Drug Class

T

he proposition appeared simple – as it turns out, deceptively so. The oncology community was a bit disheartened when the much anticipated results of a phase 3 trial by Dr Joyce O’Shaughnessy did not replicate the success of her phase 2 study1 in which the PARP inhibitor iniparib was used in combination with chemotherapy, resulting in improved outcomes for women with metastatic triple- negative breast cancer.

Hopes for the phase 3 study were high since PARP inhibitors are especially well suited for victims of this lethal form of breast cancer.

It is useful to call to mind that this is personalized medicine we are dealing with: the up-close-and-personal exploration of the mechanics of tumor DNA destruction and the body’s vast arsenal of enzyme wizardry trying its best to repair broken single and double strands of DNA. Cancer revolves around nature’s misguided attempt to protect damaged DNA and prevent cell death – even the cell death of the body’s worst enemy. So it is somewhat naive to elevate hopes to expectations at this early stage of research of this young class of agents in an equally young category of breast cancer. How young? “A PubMed search of the medical literature shows that the first mention of ‘triple-negative’ breast cancer was in October 2005.”2 Dig a little deeper and we discover that “Many cancers meet the definitions of both triple-negative breast cancers and basal-like breast cancers.”2 In fact, experts for a time claimed that triple-negative cancers and basal-like phenotypes are basically identical,3,4 but this was overturned: “...clinical, microarray, and immunohistochemical data show that this is not the case.”2 Similarly, PARP inhibitors had only begun to show up in clinical trials around 2009,5 and Foulkes and colleagues join the ranks of researchers who regard them as our best hope for triple-negative breast cancer: “PARP inhibitors and other targeted agents are now at the forefront of clinical research on the treatment of triple-negative breast cancer.”2 Alright...let’s try to connect some of the dots. First of all, patience rather than dismay might be a more reasonable response to the inconsistent outcomes here.

We are not in a state of disarray because the outcomes of the first study were not replicated in the next one.

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The reason may involve a stunning, singularly humbling statement that we find in the conclusion of Foulkes’ article. At the end of his brilliant coverage of the forces in play in triple-negative breast cancer, he mentions a pathophysiologic fact of staggering significance almost as an aside. Triple-negative breast cancer and Robert E. Henry its symptomatically look-alike disease state, basal-like breast cancers, have been keeping a secret from patients, researchers, oncologists, payers, and pharmaceutical companies seeking to distill a cure.

To wit: each of these disease states are probably not “... single entities but rather are a collection of different diseases. Hence, studies that address the molecular underpinning of this heterogeneity and attempt to identify the drivers of therapeutically relevant subgroups of triple-negative and basal-like breast cancers are warranted.”2,6 Now that is worth a double take. We’ve been

“PARP inhibitors and other targeted agents are now at the forefront of clinical research on the treatment of triple-negative breast cancer.” given a clue worth following up in our search for the slip twixt phases 2 and 3 trials of the PARP inhibitor – which has been sent out on the mission to combat one disease state, only to find a cluster of them, each with its own pathophysiologic actions. Imagine the possibilities, the detours awaiting the PARP inhibitor as it wends its way through a cluster of diseases. So perhaps the faith placed in PARP inhibitors is not misplaced after all, when what we are facing is a far more complex entity than anticipated. And so, expectations for pinpoint accuracy in back-to-back trials treating a disease state that isn’t a single disease are seen to be premature at best. We have much to learn, and there is no reason to think we are on the wrong track using PARP inhibitors. More likely we are facing a situation

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of finding the specific patient subset that will be responsive to them. More tests, please.

The O’Shaughnessy phase 3 study holds a meaningful lesson for all involved in personalized medicine’s targeted approach to cancer treatment. There is value in looking beyond the empirical results of trials. A careful examination of the designs of each study is in order

The more things change, the more they remain the same. Personalized medicine is just our new medicine. As with all medical advancement, it should be approached with caution and intellectual humility, not assumptions of success. to learn if differences in method account for the different results. Assumptions of PARP inhibitor ineffectiveness are unwarranted, and expectations should be replaced by patient review of results. This “failure” is really just a signpost on a road that may lead to successful use of PARP inhibitors. It suggests a need for becoming familiar with the biological mechanics of triple-negative breast cancer and the pharmacodynamics of this new targeted therapy for it. This column has not yet touched on the nuances of PARP inhibitors – which make fascinating reading in themselves, to be sure! Space prohibits doing justice to them and explaining why they are being studied so vigorously.

Our next column will focus on triple-negative breast cancer’s multifaceted disease state and discuss the specifics of PARP inhibitors, the unofficial drug of choice for this unconventional disease state. Suffice it for now to say that this confidence appears valid – odd as it may seem to place confidence in anything involved in this cutting-edge field of diagnosis and treatment. There is substantial cause for hope for this class of drugs in triple-negative breast cancer, once we reexamine the clinical trial designs employed. As promised, specifics concerning this drug class shall occupy our energies in the next column.

A closing sentiment involves a statement delivered at a news conference years ago by Dr John Henry Laragh,

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the researcher credited with discovering the renin-angiotensin-aldosterone hormonal control system as the basis for hypertension. Extrapolate his point of reference a bit, and the relevance of his wisdom to the current matter becomes clear: “Risk factors are indicative of our ignorance, not our knowledge. A disease has one cause, not several. Thus, if we knew the cause of the disease, we would not be exploring multiple risk factors, only the one producing the condition. But we do not possess that knowledge, and so we cast a wide net. Let us therefore advance our propositions with intellectual humility and remain open to alternative schools of thought.”

The more things change, the more they remain the same. Personalized medicine is just our new medicine. As with all medical advancement, it should be approached with caution and intellectual humility, not assumptions of success, following Dr Laragh’s refreshing advice. We do better to make use of emerging research, learning continually about the biological basis of cancers, and maintaining composure when results depart from expectations as we endeavor to heal with new personalized medicine techniques and drugs. Patients deserve our diligence and humility – a rational and productive package. So before expressing dismay over the first disappointing study on PARPs, we may also want to consider advice offered in The Hitchhiker’s Guide to the Galaxy...“Don’t Panic!” Personalized medicine, after all, is quite a big galaxy. u

Robert E. Henry

References

1. O’Shaughnessy J, Osborne C, Pippen JE, et al, Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205-214.

2. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938-1948.

3. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360:790-800.

4. Kreike B, van Kouwenhove M, Horlings H, et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas.

Breast Cancer Res. 2007;9:R65.

5. Alli E, Sharma VB, Sunderesakumar P, et al. Defective repair of oxidative DNA damage in triple-negative breast cancer confers sensitivity to inhibition of poly(ADP-ribose) polymerase. Cancer Res. 2009;69:3589-3596.

6. Ossovskaya V, Li L, Broude EV, et al. BSI-201 enhances the activity of multiple classes of cytotoxic agents and irradiation in triple negative breast cancer. In: Program and abstracts of the American Association for Cancer Research Annual Meeting; April 18-22, 2009; Denver, CO. Abstract 5552.

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Now enrolling Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial.

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

To learn more about this study, please visit www.ClinicalTrials.gov.

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The Global Biomarkers Consortium, a community of worldrenowned oncologists, will convene to better understand the clinical application of predictive molecular biomarkers and further personalize care for patients with cancer. The rapidly expanding pool of predictive molecular biomarkers has ushered in the era of personalized medicine for cancer patients. It is clear that practicing oncologists and hematologists, oncology nurses, and oncology pharmacists, who make up the interprofessional team responsible for the management of patients with cancer, must be knowledgeable regarding existing and emerging biomarkers and which have been shown to be of value in guiding personalized therapy for their patients.

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testimonials The Global Biomarkers Consortium Inaugural Meeting held this past year in Orlando was a wonderful opportunity to think about myeloma and other cancers from a different perspective. Typically we focus on treatment and outcomes from a purely drug-specific approach, but this meeting offered each of the diseases discussed a chance to segment the disease, and then think about treatment and outcomes. These types of presentations bring new clarity to how we treat and diagnose cancer, and really help to focus on the future of oncology.

– Sagar Lonial, MD Emory University

I think the main differentiating factor of this meeting is its multidisciplinary, multicancer format which brings together groups of people that don’t usually talk to each other. Also the topics are very unique and the whole concept of biomarkers in cancer is a “hot” topic.

– Sanjiv Agarwala, MD St. Luke’s Cancer Center

who attends GBC Primary site of practice

Profession 10.3%

13%

10.3%

45%

Academic clinical practice

29% 16.1% MD/DO

24.1%

PhD

Community hospital

RN/APN

Private practice

RPh/PharmD

6.4%

Pharmaceutical industry Other

New patients seen per week

Professional experience

26.7%

12.9%

22.6%

Other

10.3%

Academic research only

33.3%

56.7%

20%

1-3years years 1-3 3-5years years 3-5

6.7% 3.2% 6.7%

5-10years years 5-10

1-5 1-5 5-10 5-10

26.7%

10-20years years 10-20 >20years years >20

www.globalbiomarkersconsortium.com

20%

10-15 10-15 >15 >15