PMO August 2013

August 2013 Volume 2 • Number 5 A Peer-Reviewed Journal

The official publication of

Global biomarkers Consortium Clinical Approaches

PM O TM

to Targeted Technologies

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Personalized Medicine in Oncology TM

RENAL CELL CARCINOMA Antiangiogenic Tyrosine Kinase Inhibitors and Their Diverse Spectra of Inhibitory Activity: Implications for Personalized Therapy in Renal Cell Carcinoma……........................ Page 243

INTERVIEW WITH THE INNOVATORS Providing Molecular Profiling for Patients With Ovarian Cancer: An Interview With Laura Shawver, PhD, of The Clearity Foundation...................Page 254

MULTIPLE MYELOMA: CME Considerations in Multiple Myeloma. Ask the Experts: Combination Versus Sequential Therapy.....................................................Page 262

IMMUNOTHERAPY Immune-Related Endocrinopathies Associated With Ipilimumab Therapy.......................... Page 270

ALSO IN THIS ISSUE… • The Last Word by Robert E. Henry.........Page 289

Implementing the Promise of Prognostic Precision into Personalized Cancer Care

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

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.

B:11.25”

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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.

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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.

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Antiangiogenic Tyrosine Kinase Inhibitors and Their Diverse Spectra of Inhibitory Activity: Implications for Personalized Therapy in Renal Cell Carcinoma PAGE 243 Sanjiv S. Agarwala, MD; Michael K. K. Wong, MD, PhD, FRCPC The authors discuss the potential benefit of using detailed molecular tumor profiling in patients with renal cell carcinoma.

INTERVIEW WITH THE INNOVATORS Providing Molecular Profiling for Patients With Ovarian Cancer: An Interview With Laura Shawver, PhD, of The Clearity Foundation

PAGE 254 PMO speaks with Dr Laura Shawver, biotechnology entrepreneur, The Clearity Foundation founder, and ovarian cancer survivor, about the challenges in profiling ovarian cancers, translational research, and her experience as a patient.

MULTIPLE MYELOMA: CME Considerations in Multiple Myeloma. Ask the Experts: Combination Versus Sequential Therapy PAGE 262

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Volume 2 • No 5

Ajay K. Nooka, MD, MPH, FACP; Charise Gleason, MSN, ANP-BC, AOCNP; Katherine Sanvidge Shah, PharmD, BCOP

IMMUNOTHERPAY Immune-Related Endocrinopathies Associated With Ipilimumab Therapy

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Le Min, MD, PhD; Nageatte Ibrahim, MD

Case Study: Management of IpilimumabAssociated Endocrinopathy

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Strategic Editor Robert E. Henry

News From ASCO

Senior Copy Editor BJ Hansen

PAGE 284

ASCO President Focuses on Bridges to Conquer Cancer Ten Years of Tamoxifen Is Superior to 5 Years in ER+ Breast Cancer Multiple Myeloma: Novel Agents Emerge in Initial Therapy, Refractory Setting

Copy Editor Rosemary Hansen Production Manager Marie RS Borrelli The Lynx Group President/CEO Brian Tyburski

THE LAST WORD Immunotherapy in Cancer Care: Personalized or Population-Based Medicine…and the Janusian Factor PAGE 289

Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore

Robert E. Henry Mr Henry discusses the use of immunotherapies in personalizing care.

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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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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.

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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.

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.

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Editorial Board

Editor in Chief Al B. Benson III, MD Northwestern University Chicago, Illinois

SECTION EDITORS Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida

Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee

Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts

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

Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut

Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

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

Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana

EDITORIAL BOARD Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

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

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

Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan

Hope S. Rugo, MD University of California, San Francisco San Francisco, California

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

Howard L. Kaufman, MD Rush University Chicago, Illinois

Danielle Scelfo, MHSA Genomic Health Redwood City, California

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

Katie Kelley, MD UCSF School of Medicine San Francisco, California

Lee Schwartzberg, MD The West Clinic Memphis, Tennessee

Kenneth Bloom, MD Clarient Inc. Aliso Viejo, California

Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota

John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas

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

Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington

Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts

Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Afsaneh Motamed-Khorasani, PhD Radient Pharmaceuticals Tustin, California

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio Stephen Gately, MD TGen Drug Development (TD2) Scottsdale, Arizona Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

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Gene Morse, PharmD University at Buffalo Buffalo, New York

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

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

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

Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland

David A. Proia, PhD Synta Pharmaceuticals Lexington, Massachusetts

Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

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

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SCIENTIFIC CONFERENCES 2013-2014:

Advances in Ovarian Cancer Research: From Concept to Clinic Co-Chairpersons: David G. Huntsman, Douglas A. Levine, and Sandra Orsulic September 18-21, 2013 • Miami, FL Frontiers in Basic Cancer Research Chairperson: Scott W. Lowe Co-Chairpersons: Joan S. Brugge, Hans Clevers, Carol L. Prives, and Davide Ruggero September 18-22, 2013 • National Harbor, MD Advances in Breast Cancer Research Co-Chairpersons: Carlos L. Arteaga, Jeffrey M. Rosen, Jane E. Visvader, and Douglas Yee October 3-6, 2013 • San Diego, CA 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

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 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 AACR-IASLC 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 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 RAS Co-Chairpersons: Dafna Bar-Sagi, Channing Der, and Frank McCormick February 24-27, 2014 • Lake Buena Vista, FL AACR Annual Meeting 2014 Chairperson: Scott W. Lowe April 5-9, 2014 • San Diego, CA

Letter From the Board

The Role of Immunotherapies in Personalized Medicine Dear Colleague, s personalized medicine (PM) continues to expand its presence in cancer care, the need for clarity of its mission increases along with it. In this issue of Personalized Medicine in Oncology (PMO), we examine the expansion of immunotherapy in The Last Word column (page 289), which draws out the need for clarity on whether immunotherapy and PM belong in the same sentence. While antigen-specific immunotherapy may be the ultimate personalized therapy, the greatest recent strides have come in the use of immunotherapeutic agents without apparent patient or antigen specificity. It is believed that the patient’s immune system is poised to mount an antigen-specific response to agents such as interleukin-2 Kim Margolin, MD and ipilimumab as well as to investigational checkpoint blocking agents such as nivolumab and lambrolizumab. Also, at least in the preclinical setting, immunotherapy and molecularly targeted therapy appear to complement each other’s mechanisms and may possess therapeutic synergy, making them essentially “joined at the hip.”

The anti–CTLA-4 antibody ipilimumab has achieved a significant increase in survival for patients with metastatic melanoma. In a study of immunotherapy, Mellman, Coukos, and Dranoff note that the success of immunotherapy is happening “…together with the advent of targeted therapies…,” working with it “… to obtain a durable and long-lasting response in cancer patients.” The authors hold that these non-PM drugs are succeeding with the help of PM. All advances in cancer therapy, be they empirically personalized or otherwise, rely on PM to achieve optimal outcomes. In short, nothing moves in cancer care any longer without reference to PM. This de facto synergy between targeted and other medications is telling today’s clinicians to look to PM whenever possible to strengthen the regimen. But the picture is far from clear, and the criteria for what constitutes PM treatment are often lost on the busy oncologists urgently pursuing a treatment strategy that will save the patient. Keeping oncologists focused on the advantages of PM therapies and diagnostics and how best to use them is essential to avoid limiting their utilization.

The goal of PMO is to open up the nuances of PM to our readership, keeping you focused on the continued importance of PM to your patients. The recent crush of attention toward the new immunotherapies underscores why our continued coverage of PM is so necessary. For nothing surpasses the value of enriched, targeted treatment, and physicians must constantly hone their expertise in PM care strategies, even when conventional treatments are introduced. PM and non-PM therapies will continue to coexist for the foreseeable future, requiring all the more working knowledge on the part of oncologists to understand the value that PM brings to treatment.

A

Sincerely,

Kim Margolin, MD University of Washington/Fred Hutchinson Cancer Research Center PMO Board Member

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PMPM O C

ERSONALIZED EDICINE IN ONCOLOGY

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Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

ALL FOR PAPERS

Personalized Medicine in Oncology’s mission is to deliver practice-changing information to clinicians

about customizing healthcare based on molecular profiling technologies and each patient’s unique genetic blueprint.

Our vision is to transform the old medical model of stratified medicine into a new model of personalized care where all decisions and practices are tailored to the individual.

The goal of Personalized Medicine in Oncology is to sensitize practitioners to the performance realities of new diagnostic and treatment discoveries and to clarify molecular profiling technologies as they relate to diagnostic, prognostic, and predictive medicine. PMO will feature diagnostic and clinical treatment information concerning these 3 root aspects of personalized medicine in oncology.

Readers are invited to submit articles for consideration in the following categories:

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Presentation of emerging clinical data

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Genetics and Biomarkers •

Exploring genetic discoveries and impact on predictors of disease and therapeutic response

The Cost of Personalized Medicine •

Personalized medicine policy drivers

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Payer coverage of diagnostics and biologics

Genetic Profiling Technologies •

What technologies are available to clinicians and consumers and their impact on diagnostic, prognostic, and predictive medicine

In Practice •

A practical guide for community-based oncologists discussing clinical applications and strategies for incorporating personalized medicine techniques into practice

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Development of treatment algorithms

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Case studies, patient-reported outcomes, defining treatment goals, partnering with patients and caregivers

Submit the entire manuscript and a cover letter stating the objectives of the article to PMO@greenhillhc.com.

Manuscripts should follow the Author Guidelines available at www.PersonalizedMedOnc.com.

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ASK THE EXPERTS: Maintenance Settings 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 Rattanonont Ferris Vice President of Finance Andrea Kelly Director of Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore

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

Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean

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

Houry Leblebjian, PharmD, BCOP Clinical Pharmacy Specialist in MARCH 2013 • VOLUME 4 • NUMBER 2 Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

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Discussions in Personalized Treatment for Lymphoma: Do We Have Consensus?

CONTRIBUTING FACULTY Chair Stephanie A. Gregory, MD

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Associate Professor Section of Hematology/Oncology Director, Lymphoma Program The University of Chicago Medical Center Chicago, IL

Mitchell R. Smith, MD, PhD Director of Lymphoid Malignancies Program Taussig Cancer Institute Cleveland Clinic Cleveland, OH

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Assistant Attending Medical Oncologist Lymphoma, Cutaneous Lymphomas, T-Cell Lymphoma Memorial Sloan-Kettering Cancer Center New York, NY

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Renal Cell Carcinoma

Antiangiogenic Tyrosine Kinase Inhibitors and Their Diverse Spectra of Inhibitory Activity: Implications for Personalized Therapy in Renal Cell Carcinoma Sanjiv S. Agarwala, MD Department of Oncology and Hematology St. Luke’s Cancer Center, Bethlehem, Pennsylvania Michael K. K. Wong, MD, PhD, FRCPC University of Southern California, Keck School of Medicine Division of Medical Oncology, Norris Comprehensive Cancer Center, Los Angeles, California

Key Points • Introduction of multiple VEGFR TKIs with slightly different inhibition profiles lends itself to increasingly personalized treatments • Tumor heterogeneity may complicate this approach • Multiple biopsies may better determine the overall mutational burden of an RCC tumor, but this strategy is hampered by practical limitations and cost of technology • We are in a unique position to potentially derive therapeutic benefit for RCC using detailed molecular tumor profiling

T

umor angiogenesis is the biologic process by which tumors induce host production of functional blood vessels. Antiangiogenic therapy exploits a critical need for angiogenesis because, in its absence, solid tumors cannot grow or metastasize. Despite this, antiangiogenic monotherapy has provided little or no clinical benefit in many solid tumor types.

One notable exception is renal cell carcinoma (RCC) – a highly vascularized tumor. The unique vas-

cularization of RCC allows easy escape from the kidney to establish metastases throughout the body and accounts for the high morbidity and mortality rates associated with this tumor type. This phenotype is driven by mutation of the von Hippel-Lindau (VHL) tumor suppressor gene that is present in the clear cell histological subtype, which constitutes approximately 85% of RCCs.1,2 VHL inactivates hypoxia-inducible factor – a transcription factor that, when induced, upregu-

Dr Agarwala is Professor of Medicine at Temple University School of Medicine in Philadelphia and Chief of Oncology & Hematology at St. Luke’s Cancer Center in Bethlehem, Pennsylvania. He received his degree and completed an internship and residency at the G.S. Medical College and King Edward Memorial Hospital in Bombay, India. He also completed residency training in internal medicine and a fellowship in hematology-oncology at the University of Pittsburgh School of Medicine. He is a nationally recognized expert in the treatment of metastatic melanoma.

Dr Wong is Professor of Medicine, Head of the Solid Tumors Section, and leads the Melanoma Program at USC Norris Comprehensive Cancer Center and Hospital in Los Angeles, California. He has a PhD in experimental pathology and was a National Cancer Institute of Canada Postdoctoral Scholar in the molecular biology of angiogenic cytokines. His research has focused on angiogenesis, immunomodulation, and tumor-matrix interactions.

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Renal Cell Carcinoma

multiple antiangiogenic tyrosine kinase inhibitors (TKIs) are approved for treatment or are in clinical development. Although VEGF inhibition is the key contributor to the clinical activity of these agents, TKIs also target additional angiogenic pathways.

Proangiogenic Signaling Pathways With Importance in Tumor Angiogenesis

Sanjiv S. Agarwala, MD

Michael K. K. Wong, MD, PhD, FRCPC

lates potent proangiogenesis genes, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).3,4 Hypoxia-inducible factor is activated in response to hypoxia, ultimately triggering vascular development and elevating hemoglobin levels and blood flow. Thus, when mutated, VHL loses its counterbalancing function, and hypoxia-inducible factor activity leads to polycythemia and the vascularized RCC phenotype.

FGF signaling modulates bone growth, wound healing, and nerve regeneration, and its role in angiogenesis and tumor growth is well established.

Multiple pathways contribute to angiogenesis in vascularized tumors, either by directly stimulating vascular endothelial cell (EC) function or indirectly by recruiting/stimulating cells that support angiogenesis.

For example, VEGF and angiopoietin-Tie (Ang-Tie) signaling directly stimulates ECs, whereas PDGF and fibroblast growth factor (FGF) pathways predominantly affect the pericytes and stromal components, respectively, to induce angiogenesis.

Because of the importance of angiogenesis in RCC,

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VEGF is one of the most potent angiogenic pathways and consists of 6 ligands (VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and placental growth factor) and 3 receptors (VEGFR-1, VEGFR-2, and VEGFR-3).5 Of these, VEGFA and VEGFR-2 appear to have the most dominant roles in tumor angiogenesis. VEGFRs are expressed on the surface of ECs and promote downstream intracellular signaling through the mitogen-activated protein kinase (MAPK) and phosphoinositol-3-kinase/ mammalian target of rapamycin (PI3K/mTOR) pathways when activated.6 This signaling ultimately promotes vascular permeability, EC migration, and cell growth and survival.7 Development of agents targeting VEGF signaling represented a major breakthrough in antiangiogenic therapy, and this pathway remains the primary focus of antiangiogenic research (Figure 1).

The Ang-Tie pathway is critical for normal angiogenic processes in embryos and adults and also contributes to tumor angiogenesis. Ang-Tie signaling involves 4 angiopoietin growth factors (Ang1, Ang2, Ang3, and Ang4) and their receptors (Tie1 and Tie2).8 Ang1 and Ang2 both bind to Tie2 but mediate different effects.

Ang1, which is mainly expressed by perivascular cells, seems to primarily induce vascular maturation and homeostasis, whereas Ang2, which is expressed with Tie2 primarily by ECs, appears to mediate vascular destabilization and vessel sprouting. In contrast to the VEGF pathway, which mainly operates early in vessel development, Ang-Tie signaling functions in late vessel maturation and stabilization.8 Its functions in tumor vasculature, however, are incompletely understood (Figure 1).

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Figure 1. Pathways With Importance in Tumor Angiogenesis Figure 1

TUMOR CELL

Tumor Cell Growth, Survival, and Migration

GF

PD

VEGFR FGFR

PERICYTE

VE

GF

RAS RAF FAK

FGF

MEK

FGFR RAS

PI3K

PLCɣ

STAT

PLCɣ

AKT

Tie2

Ang1 ERK

PI3K

mTOR

RAF PIP2

PIP2

MEK

AKT

DAG

Ca++

Cellular Proliferation and Migration

mTOR

PIP3

ERK

PKC

Protein Translation

ERK

VEGF

ENDOTHELIAL CELL

RAF

MEK

Vascular Permeability

VEGFR

Migration

Ang1

FGF

VE

RAS PLCɣ

Ang2

FGF

Cytoskeletal Rearrangement

PDGFR

GF

ANGIOGENESIS Target Gene Expression

Mutations within the Von Hippel-Lindau (VHL) pathway result in overactivation of the VEGF and mTOR pathways that drive renal cell carcinoma. Alternative proangiogenic pathways are thought to represent possible escape mechanisms from primary VEGF inhibition.

Ang1 indicates angiopoietin 1; Ang2, angiopoietin 2; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; FGF(R), fibroblast growth factor (receptor); MEK, mitogen-activated protein/extracellular signal-regulated kinase; mTOR, mammalian target of rapamycin; PDGF(R), platelet-derived growth factor (receptor); PI3K, phosphoinositol-3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLCγ, phospholipase C-γ; VEGF(R), vascular endothelial growth factor (receptor).

The FGF pathway has a larger biological footprint: 18 to 23 ligands and 4 receptors (FGFRs 1-4) that can undergo alternative splicing to generate multiple isoforms.9 FGF signaling modulates bone growth, wound healing, and nerve regeneration, and its role in angiogenesis and tumor growth is well established (Figure 1). MAPK, PI3K, and protein kinase C are the primary transducers of FGF signaling and modulate downstream

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gene expression. ECs express high levels of FGFRs 1 and 2, which are activated primarily by FGFs 1 and 2, resulting in EC proliferation and migration, extracellular matrix degradation, alteration of intercellular adhesion, and communication. Unlike VEGFR, which is fairly restricted to the endothelial compartment, FGFRs are also found on stromal cells and can participate in remodeling of the host microenvironment.

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X X

X X

X Vandetanib49 (ZD6474)

Nintedanib (BIBF 1120)46

X X

X

X

X

X X X X Tivozanib (AV-951)43

Dovitinib (TKI258)38

Axitinib

34

30

Pazopanib

Sorafenib

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c-KIT indicates stem cell factor receptor; CSF-1R, colony-stimulating factor 1 receptor; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; FLT3, FMS-like tyrosine kinase 3; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor.

X X

X X X X X X X X

X X X

X X X

X X X

X X X Sunitinib

20

Approved

Not Currently Approved

X X

X

X

X

X

X

X X X

X

X

X

X

X

X

X

X

c-KIT FLT3 RAF RET EGFR 15

FGFR-1 FGFR-2 FGFR-3 VEGFR-1 VEGFR-2 VEGFR-3 PDGFR-α PDGFR-β CSF-1R

Table. Tyrosine Kinase Inhibitors Approved or Investigated in Renal Cell Carcinoma 246

PDGF initially achieved prominence for its role in remodeling the vascular wall during atherosclerosis. PDGF signaling consists of 5 isoform ligands (PDGFA, PDGFB, PDGFC, PDGFD, and PDGF­ ­AB) and 2 receptors (PDGFR-α and -β) and plays an indirect role in angiogenesis by recruiting pericytes to vascular sprouts.10,11 Pericytes, which constitute an encircling layer of smooth muscle around developing vasculature, establish and maintain the integrity of vascular function by modulating ECs (Figure 1).

Although these and other pathways uniquely act to promote angiogenesis, they may also act synergistically. For instance, a positive feedback mechanism appears to exist between FGF2 and VEGF.12,13 Therefore, alternative pathways can potentially “rescue” tumor cells that have had their dominant angiogenesis pathway blocked by a TKI. Because of the emerging importance of these pathways in resistance to RCC therapy, this review highlights the diversity of pathways inhibited by these TKIs, with particular focus on non-VEGF “angiogenic” pathways. Although these agents primarily function through VEGF inhibition, their targeting of multiple kinases may provide an opportunity to simultaneously inhibit multiple pathways. This diversity was traditionally considered a negative “off-target” effect; however, we present the case that this diversity provides an opportunity to personalize the care of patients with RCC by targeting additional pathways based on the molecular characteristics of individual tumors. Whereas the RCC literature to date has been appropriately dominated by a VEGF-centric approach, this article discusses the potential to maximize response to primary therapy or, once resistance develops, to salvage treatment failure.

Targeting Proangiogenic Pathways A number of antiangiogenic therapies are approved or are under investigation for various tumor types. Many strategies to block angiogenesis have been explored, including VEGF pathway inhibitors

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that directly bind to and inactivate circulating VEGF or that inhibit VEGFR signaling. Another strategy inhibits the ability of mTOR, a master molecular switch, to downregulate the synthesis of several angiogenic factors. These approaches have been extensively studied in advanced RCC and are now considered the standard of care for this cancer. Although it is thought that these agents mainly act through antiangiogenic avenues, they may also directly inhibit tumor cell proliferation.14 Seven agents are currently approved by the FDA to treat advanced RCC.15 Four of these agents – sunitinib, sorafenib, pazopanib, and axitinib – are TKIs, for which the primary clinical mechanism of action is assumed to be VEGFR inhibition (Table). The anti-VEGF monoclonal antibody bevacizumab is approved in combination with interferon. Everolimus and temsirolimus are mTOR inhibitors. Additional agents are under investigation, most notably a number of TKIs. The remainder of this review will focus on approved and emerging TKI therapies for advanced RCC. Detailed reviews for other targeted agents in RCC were published previously.16-18

Approved TKI-Targeted Treatments for RCC Generally, TKIs bind reversibly to or adjacent to the ATP-binding site within its target, thereby inhibiting kinase activity through steric hindrance. Given that these domains are structurally similar from one kinase to another, and because inhibition is partly related to the 3-dimensional shape of the TKI, it is not unexpected that these agents may also target conserved ATP-binding sites in other kinases (Figure 2). In contrast, allosteric inhibitors, which bind to fairly unique sites outside of the kinase domain, tend to be target specific.19 Therefore, TKIs may simultaneously block kinases in multiple angiogenic pathways to delay or circumvent acquired resistance to therapy.

Sunitinib inhibits VEGFRs 1-3, PDGFR-α and -β, colony-stimulating factor 1 receptor, stem cell factor receptor (c-KIT), FMS-like tyrosine kinase 3 receptor (FLT3), and neurotrophic factor receptor.20 Sunitinib was evaluated in a phase 3 trial with 750 treatment-

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naive patients randomized to either sunitinib or interferon-α therapy.21 Compared with interferon-α, sunitinib demonstrated superior progression-free survival (PFS) (11 vs 5 months), overall survival (OS) (26.4 vs 21.8 months), and quality of life.21,22 Sunitinib has also demonstrated antitumor activity in patients with RCC who progressed after cytokine therapy.23 Sunitinib is approved and recommended for first-line use and second-line use after cytokine therapy in advanced RCC.15 Sunitinib strongly inhibits c-KIT, an oncogene involved in gastrointestinal stromal tumors (GISTs), and is also approved as GIST therapy.

Generally, TKIs bind reversibly to or adjacent to the ATP-binding site within its target, thereby inhibiting kinase activity through steric hindrance.

Sorafenib inhibits VEGFRs 1-3, PDGFR-β, c-KIT, FLT3, and RAF – an MAPK pathway intermediate.24 A phase 3 trial compared second-line sorafenib with placebo in 903 patients.25 An interim PFS analysis demonstrated the superiority of sorafenib over placebo (5.5 vs 2.8 months); thus, the protocol was amended to permit placebo-assigned patients to cross over to sorafenib. OS with sorafenib was similar to that of placebo (17.8 vs 15.2 months, respectively); however, a secondary analysis censoring crossover patients revealed an OS benefit favoring sorafenib (17.8 vs 14.3 months).26 Sorafenib was also active in the third-line setting after first-line sunitinib and second-line temsirolimus or everolimus.27 In the first-line setting, a phase 2 trial demonstrated greater tumor shrinkage and a higher quality of life with sorafenib versus interferon-α. However, median PFS was similar between arms (5.7 months for sorafenib, 5.6 months for interferon-α).28 Sorafenib therapy is approved and recommended for use as second-line treatment after progression on cytokine or TKI therapy in advanced RCC15 and is also approved for use in unresectable hepatocellular carcinoma (HCC). Importantly,

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in HCC, the clinical activity of sorafenib may result from both antiangiogenic activity and inhibition of RAF-dependent and -independent pathways.29 Pazopanib inhibits VEGFRs 1-3, PDGFR-α and -β, and c-KIT.30 A phase 3 trial compared the efficacy of pazopanib with that of placebo in treatment-naive (n=233) and cytokine-pretreated (n=202) patients with advanced RCC.31 Pazopanib demonstrated superior PFS over placebo in the overall population (9.2 vs 4.2 months), the treatment-naive population (11.1 vs 2.8 months), and the cytokine-pretreated population (7.4 vs 4.2 months). Although OS was similar in both arms as a result of patient crossover, analyses to censor for crossover suggested an OS benefit with pazopanib.32 Pazopanib is approved in advanced RCC and is recommended in the first-line setting and in the second-line setting after cytokine therapy.15 Pazopanib is also approved for patients with advanced soft tissue sarcoma after chemotherapy.33 Axitinib inhibits VEGFRs 1-3, with one of the highest in-class potencies, and also inhibits PDGFR-α and -β and c-KIT.34 For these reasons, the use of axitinib as a salvage TKI was thought to be a promising strategy.

A phase 3 trial evaluated second-line axitinib versus sorafenib in 723 patients with RCC.35 Compared with sorafenib, axitinib significantly prolonged median PFS (6.7 vs 4.7 months) and was associated with a greater delay in time to symptom worsening. These results suggest that a more potent inhibition of VEGFR may induce a more robust clinical outcome in the salvage setting. Another phase 3 study compared axitinib with sorafenib in 288 treatment-naive patients and showed a nonsignificant increase in PFS for axitinib (10.1 vs 6.5 months).36 Axitinib is currently approved for advanced RCC after the failure of a prior systemic therapy.

In summary, a detailed analysis of these agents showed a cross-section of inhibition involving not only different classes of angiogenesis-related receptors but different classes of kinases in general (Figure 2); individual agents differed in their avidity toward target kinases.37 This diverse spectrum of activity most likely accounts for the differences in efficacy against different

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cancers, independent of antiangiogenic effects. This focus on target diversity carries through to the agents under discussion below.

TKIs Under Investigation in RCC Dovitinib (TKI258) inhibits VEGFRs 1-3, PDGFR-β, colony-stimulating factor 1 receptor, c-KIT, FLT3, and FGFRs 1 and 3.38 A phase 1/2 trial investigated dovitinib in patients with advanced RCC or metastatic RCC (mRCC) previously treated with a VEGFR (sunitinib and/or sorafenib) and/or an mTOR inhibitor.39,40 This trial is particularly interesting because it tested a major working hypothesis regarding resistance to antiangiogenic therapy, ie, that alternative angiogenic pathways such as FGF underlie tumor escape from anti-VEGF therapy. Indeed, baseline basic plasma FGF levels were elevated in patients who previously received anti-VEGF therapies. Preliminary analysis of 59 patients revealed the antitumor efficacy of dovitinib; 3.4% achieved a partial response (PR), and 49.2% and 27.1% achieved stable disease lasting ≥2 and ≥4 months, respectively.40 Preliminary median PFS and OS of 5.45 and 11.79 months, respectively, were reported. A phase 3 trial comparing dovitinib with sorafenib after the failure of antiangiogenic therapy is under way.41 Ongoing trials are studying dovitinib for HCC, endometrial cancer, adenoid cystic carcinoma, GIST, glioblastoma, non– small cell lung cancer (NSCLC), breast cancer, gastric cancer, and prostate cancer.42 The activity of dovitinib in tumors that are not strong candidates for anti-VEGF therapies but instead rely on FGF signaling may be interesting.

Tivozanib (AV-951) is a potent inhibitor of VEGFRs 1-3 and also targets c-KIT and PDGFR-β.43 In a development plan mimicking the potent inhibitor axitinib, a phase 3 trial compared tivozanib versus sorafenib in treatment-naive and pretreated patients with advanced RCC. Tivozanib significantly improved median PFS over sorafenib (11.9 vs 9.1 months).44 A phase 2 discontinuation study in 272 patients with advanced RCC or mRCC also demonstrated the activity of second-line tivozanib, yielding 1 complete response

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Figure 2. Kinase Inhibition Profiles Figure 2 Sorafenib

Sunitinib TKL

TK

STE

Pazopanib

TKL

TK

STE

CK1

OTHER

CMGC

Axitinib TK

OTHER

CMGC

CAMK

Dovitinib

TKL STE

CMGC

CAMK

Nintedanib

TKL

TK

Vandetanib

CK1

CMGC

CAMK

CAMK

Kd

TKL

TK

STE

OTHER

CMGC

CAMK

TKL

CK1

OTHER

CMGC

CAMK

TK

STE

CK1

OTHER

STE

CK1

CK1

OTHER

TKL

TK

1 nM

STE

10 nM

CK1

100 nM 1 µM 10 µM

OTHER

VEGFR2 CMGC

CAMK

Inhibition profiles for select tyrosine kinase inhibitors (TKIs) discussed in this article were mapped onto a kinase dendrogram. Individual kinases were grouped with related kinases. The size of the red dots denotes the degree of inhibition at that particular target. Note the tremendous diversity of targets and the differences between the TKIs designed to target vascular endothelial growth factor receptor (VEGFR).

AGC indicates protein kinase A, G, and C family; CAMK, calcium/calmodulin-dependent kinases; CK1, casein kinase 1-like kinases; STE, mitogen-activated protein kinases; TK, tyrosine kinases; TKL, tyrosine kinase­–like kinases.

Image generated using TREEspot Software Tool, © DISCOVERX CORPORATION 2010. Reproduced with permission of the authors from Davis MI, Hunt JP, Herrgard S, et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011;29:1046-1051.

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(CR), and 51 PRs throughout the study. Median PFS was 11.7 months.45 Tivozanib is also under investigation in NSCLC, metastatic breast cancer, colorectal cancer, and soft tissue sarcoma.42 Nintedanib (BIBF 1120) inhibits VEGFRs 1-3, PDGFR-α and -β, and FGFRs 1-3.46 A phase 1 study demonstrated antitumor activity; 1 CR and 1 PR were observed in 10 patients with advanced RCC.47 Seven patients with RCC remained on therapy for ≥5 months; 2 remained on therapy for >1 year. A phase 2 trial comparing nintedanib versus sunitinib in first-line RCC is under way (NCT01024920).42 Nintedanib is also under investigation in HCC, glioblastoma, colorectal cancer, prostate cancer, thyroid cancer, breast cancer, and endometrial cancer. Phase 3 studies are ongoing in NSCLC and ovarian cancer.42

The clinical benefit currently gained from antiangiogenic TKIs is varied. Some patients appear to be intrinsically resistant to these agents and gain no objective benefit.

Vandetanib (ZD6474) is an inhibitor of VEGFRs 2 and 3, endothelial growth factor receptor (EGFR), and neurotrophic factor receptor; it was recently approved for the treatment of medullary thyroid cancer and has also demonstrated antitumor activity in a murine RCC model.48,49 Vandetanib is under investigation in a phase 2 trial of patients with VHL-related kidney cancer (NCT00566995).42 Clinical trials are ongoing in several tumor types, including glioblastoma, breast cancer, head and neck cancer, and pancreatic cancer.42

The Diversity of Pathways Targeted

by Individual TKIs May Influence Patient Care The clinical benefit currently gained from antiangiogenic TKIs is varied. Some patients appear to be intrinsically resistant to these agents and gain no objective benefit from treatment. In contrast, impressive response rates were observed in clear cell RCC, which

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is dependent on the VEGF pathway. However, the clinical benefit is transient, and progression typically occurs after an initial response.50 The emerging TKIs described herein hit novel targets in different combinations and may have improved utility in the clinic because their inhibitory spectra expand beyond targeting angiogenic receptors to also inhibit intracellular protumor signaling. In other tumor types, the non-VEGF inhibitory activities of TKIs are important and appear to contribute to clinical benefit. For instance, patients with specific GIST genotypes have shown improved outcomes with sunitinib treatment. This highlights the utility of sunitinib in also attacking the “off-target” c-KIT pathway.51 Patients with HCC whose tumors expressed high levels of activated extracellular signal-regulated kinase, an MAPK intermediate, achieved a longer time to tumor progression with sorafenib than did patients with low levels of activated extracellular signal-regulated kinase, which suggests an improved response to sorafenib when it can inhibit the MAPK pathway.52 In addition, the diversity of TKI targeting is notably important within nonvascular compartments of malignant tumors. Tumor cells do not readily express VEGFRs but do rely on growth pathway signaling. One working model predicts that mTOR inhibitors function both in tumor and vascular ECs. Thus, TKIs that inhibit multiple pathways might target both cell types.

The hypothesis that the diversity of tyrosine kinase inhibition affects clinical benefit may be applied to RCC and suggests that the efficacy of an agent in RCC may not depend solely on its specificity for the VEGF pathway. Comparison of a “strong” VEGFR inhibitor (eg, axitinib) with a “weak” one (eg, sorafenib), as was done in the AGILE 1051 study, would provide insight about this hypothesis. In this randomized phase 3 trial, 280 treatment-naive patients with advanced RCC were assigned to either sorafenib or axitinib. Recently reported results show that the primary end point, PFS, was not significantly different between these therapies.36 These findings suggest that factors other than the potency of VEGF inhibition contributed to clinical efficacy in this setting.

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The use of a TKI with the capability to inhibit “off-target” proto-oncogenic pathways may also be advantageous in settings of acquired resistance. Resistance to anti-VEGF therapies is not likely due to the accumulation of mutations in the EC VEGF pathway, because ECs are host-derived, end-differentiated, nonclonal cells that possess neither genomic instability nor the promiscuous gene expression inherent in tumor cells. Instead, adaptive resistance likely occurs through other means, including activation of alternative proangiogenic pathways within tumor cells. Targeting alternative pathways may help delay acquired resistance or treat resistant disease. For example, a retrospective evaluation of 216 patients with mRCC who progressed on first-line anti-VEGF therapy demonstrated that some patients still obtained benefit after receiving a second-line VEGF TKI.53 This suggests that the nonVEGF inhibitory activities of TKIs are important and may contribute to the benefit observed. Moreover, resistance to one TKI may not imply cross-resistance to another TKI with a different “off-target” profile.

Likewise, the concept of switching TKI therapies can extend even further into the treatment time line. For instance, third-line sorafenib has demonstrated activity after first-line sunitinib and second-line temsirolimus or everolimus.27 Unfortunately, limited clinical trial data exist concerning the effective sequencing of TKIs.15 Thus, sequencing decisions are driven by anecdotes and user experience, putting a heavier onus on basic and translational science data to drive the field.

To maximize the targeting of multiple pathways and gain further clinical utility, one rational strategy involves combining a TKI with another biological inhibitor or combining TKIs with complementary inhibition profiles. In support of this idea, cediranib – a VEGF TKI that is not currently under investigation in RCC – in combination with the EGFR inhibitor gefitinib yielded PRs in 6 of 18 patients with RCC in a phase 1 trial.54 It is important to note, however, that toxicity may limit these combination approaches.55,56 Another therapeutic strategy combines TKIs with other treatment modalities. Although bevacizumab has

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been added to chemotherapy without increasing toxicity,57,58 combining TKIs with chemotherapy may be more difficult and may require extensive clinical evaluation to determine optimal dose levels and schedules.

Notably, several clinical trials exploring these regimens have been discontinued.42 Combining TKIs with surgical resection may also provide additional benefit. However, this approach has raised concern, because VEGF inhibition could negatively affect perioperative wound healing. Nonetheless, recent work has demonstrated that surgery after VEGF-directed therapies can be safe if an appropriate amount of time passes between treat-

The use of a TKI with the capability to inhibit “off-target” proto-oncogenic pathways may also be advantageous in settings of acquired resistance. ment and surgical procedures.59 Furthermore, this combination may provide substantial benefit – a subgroup of patients from the phase 2 trial of tivozanib in RCC detailed above, who had undergone nephrectomy, had the highest median PFS and overall response rate (ORR).45 Additional results may be obtained from an ongoing phase 3 trial of adjuvant axitinib versus placebo in high-risk patients with RCC (NCT01599754).42 A final approach for consideration combines immunotherapy with TKIs. Larger tumors are exquisitely dependent on blood supply and are sensitive to antiangiogenic therapy, whereas small tumors appear to survive by direct diffusion and are insensitive to antiangiogenic therapy. The opposite is true of immunotherapy, for which the antigen-excess and other immune-suppressive factors generated by large tumors result in immune tolerance, whereas smaller tumors may be more immune sensitive. Thus, TKI-induced debulking followed by immunotherapy may be advantageous and, indeed, has demonstrated notable preclinical antitumor activity.60,61 Furthermore, recent work in melanoma showed that a BRAF TKI enhanced antigen presentation and may

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increase immunoresponsiveness.62 Despite promising preclinical results, translating these strategies into the clinic may prove difficult. For example, severe cardiovascular toxicity was observed in patients with RCC who received high-dose interleukin-2 immunotherapy shortly after VEGF TKIs.63 The introduction of multiple VEGFR TKIs with slightly different inhibition profiles into the RCC pharmacopeia lends itself to a near future in which treatments will become increasingly personalized. However, tumor heterogeneity may complicate this approach.

A recent study using RCC as a model showed that genomic analyses from single biopsies grossly underestimated the mutational burden of RCC tumors.64 In biopsies of multiple areas within the same tumor and of metastatic sites, up to 69% of somatic mutations were not detected across all samples. Furthermore, 26 of 30 tumor samples from 4 tumors harbored divergent allelic imbalance profiles, indicating extensive intratumor heterogeneity. Multiple biopsies may better determine the overall mutational burden of an RCC tumor, but this strategy is currently hampered by practical limitations in the delivery and cost of technology. Despite these drawbacks, VEGF TKIs may be a ready-made solution to the problem of tumor heterogeneity. As the understanding of RCC mutational burden matures, TKIs with primary activity against VEGF or mTOR may be selected for treatment on the basis of their secondary inhibition of other kinase targets.

In conclusion, the plethora of drugs in the RCC pharmacopeia presents a unique situation in which agents are closely related through their dominant mechanism of action but have diverse “off-target” effects that may be useful in clinical targeting. Therefore, we are in a unique position to potentially derive therapeutic benefit for RCC using detailed molecular tumor profiling. u

Acknowledgments We thank Michelle Boehm, PhD, and Melanie Vishnu, PhD, for their medical editorial assistance with this manuscript.

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Disclosure Statement Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. MKKW received honoraria from Novartis Pharmaceuticals, Merck Pharmaceuticals, and Pfizer Pharmaceuticals.

SSA has no conflicts to report.

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64. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883-892.

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Providing Molecular Profiling for Patients With Ovarian Cancer: An Interview With Laura Shawver, PhD, of The Clearity Foundation Laura K. Shawver, PhD The Clearity Foundation San Diego, California

T

he Clearity Foundation was launched in 2008 the panel by incorporating the analysis of more than to help patients with ovarian cancer and 200 genes, most of which are correlated with new thertheir physicians make better-informed treatapies being tested in clinical trials. The combined inment decisions based on the molecular profiling of formation from the panels allows patients to prioritize tumors. The Clearity team includes from both chemotherapy agents and scientists, physicians, and volunteers the molecular targeted agents being who feel passionately that the partested in clinical trials. adigm for recurrent ovarian cancer In addition to providing access treatment needs to change from a to molecular profiling tests, Clearity trial-and-error approach to one that also provides a summary report proindividualizes therapy selection viding a consensus interpretation of based on the molecular profile of results based on published evidence each patientâ&#x20AC;&#x2122;s tumor. This nonprofit from clinical research studies as well organization provides patient support as their own ovarian cancer database, services including lab test coordinawith the intention of educating both tion, tumor blueprint interpretation, patient and physician as to how this and clinical trial identification cominformation can be used to prioritize Laura K. Shawver, PhD pletely free of charge to the patient. treatments that may be most approClearity also advocates for expeditpriate for that patient. ing the clinical development of novel targeted agents Advocacy groups such as The Clearity Foundation for ovarian cancer and has created a database that is are playing a large role in the adoption of personalized correlating tumor molecular profiles with treatment medicine techniques. Personalized Medicine in Oncoloutcomes. ogy (PMO) recognizes this role and welcomes groups The Clearity Foundation creates a molecular profile such as this to the personalized medicine community. for women with recurrent ovarian cancer by measuring We were pleased to speak with Dr Laura Shawver, a wide range of markers. The molecular tests of Clearbiotechnology entrepreneur, The Clearity Foundaityâ&#x20AC;&#x2122;s standard panel are protein assays, and the infortion founder, and ovarian cancer survivor, about the mation from these helps patients prioritize from the challenges in profiling ovarian cancers, translational approved cancer drugs. Recently, Clearity expanded research, and her experience as a patient.

Dr Shawver is the Founder of The Clearity Foundation and Chief Executive Officer of Cleave Biosciences, which is focused on developing novel drugs for difficult-to-treat cancers. She is a biotechnology entrepreneur with 25 years of scientific experience.

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PMO Thank you so much for speaking with us, Dr Shawver. To begin, can you describe how physicians access their patient’s molecular profiling?

Dr Shawver To summarize our services, when a patient works with Clearity, the first step is to gather all the necessary documents. For example, for patient consent to participate in our database, they provide authorization and release forms, and we fill in laboratory test requisitions. If a woman needs help with payment for the tests or help with her co-pays, she also fills in a simple grant application form. Our patient coordinator fills out most of the forms, often in collaboration with the oncology nurse from the physician’s office.

Next, we coordinate the shipping of the tumor block from the pathology laboratory to the CLIA [Clinical Laboratory Improvement Amendments]-certified testing facilities to ensure timely analysis of the specimens.

In addition to tumor specimens, we may be able to conduct profiling on a cell pellet from peritoneal ascites fluid or pleural effusions.

It’s worth noting that we utilize CLIA-certified laboratories and the latest technologies for molecular profiling. These laboratories and the composition of our testing panel evolve as new evidence becomes available. Our Web site provides the list of our current tests and laboratories.

After all the tests have been completed, we provide an easy-to-read report that summarizes and provides a consensus interpretation of the results from multiple laboratories to the physician. The Clearity Foundation offers assistance or consultation to interpret the information on the reports. We also track patient results and outcomes to enable improvements in results interpretation.

PMO How well or weakly established is the practice of accessing patients’ molecular profiling among oncologists?

Dr Shawver Molecular profiling in its simplest form has been used for many years to help choose the appropriate treatment for certain cancers and is now routine.

Examples include estrogen receptor protein for breast cancer: antiestrogens and aromatase inhibitors; HER2

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protein and copy number for breast cancer: trastuzumab; and c-Kit status for gastrointestinal stromal tumor: imatinib and sunitinib. And more recently, the adoption of testing for EGFR mutation for lung cancer coupled with KRAS status: erlotinib; KRAS status for colon cancer: cetuximab; ALK translocations for lung cancer: crizotinib; and BRAF status for melanoma: vemurafenib.

However, the measurement of a comprehensive panel of markers/genes to generate that profile and identify all therapy options that match the molecular characteristics of the tumor is not routine. A comprehensive panel is especially important in ovarian cancer because we are all so different.

Molecular profiling in its simplest form has been used for many years to help choose the appropriate treatment for certain cancers and is now routine.

Protein expression measured by immunohistochemical tests can also be utilized to help understand sensitivity and resistance to chemotherapy agents such as topoisomerase I (topotecan, irinotecan), topoisomerase II (anthracyclines such as pegylated liposomal doxorubicin), thymidylate synthase (antifolates such as pemetrexed), and ribonucleotide reductase M1 (nucleoside analogues such as gemcitabine).

Unfortunately, the use of molecular profiling to prioritize treatment choices – whether it’s FDA-approved agents or clinical trial agents – for recurrent ovarian cancer is limited. Oncologists have multiple choices for treatment when ovarian cancer recurs, but that choice is typically trial and error without a means to prioritize among those choices.

PMO What are the challenges to this process – either in the community or academic setting?

Dr Shawver The first challenge is that many doctors believe treatment for recurrent disease is only palliative.

Therefore, when faced with a woman battling recurrent ovarian cancer, they believe that any treatment will buy time, but that most women will die of the disease. Es-

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sentially, they give up on searching for a cure, at least for an individual. At Clearity, we want to help doctors change this by providing treatment that is prioritized based on the testing. Even chemotherapy works by interacting with specific targets in the cell. If that target is not present, the chemotherapy drug will not work.

Sometimes, if the target is present at a level that is too high, not enough of the drug can be delivered to the tumor to provide sufficient inhibition of this driver of cell growth, and the tumor is unaffected. So, our tests measure the levels of those targets with the aim of ruling out drugs that might not work and ruling in the drugs that have a better chance. By using this information to prioritize treatment options, we hope that more women will benefit and avoid drugs that would result in all the toxicity associated with those agents but provide no benefit.

Clinical trials will be needed, and the goal is to show preliminary evidence using our database that will establish the testing parameters for clinical trials.

Another challenge in this approach is that despite considerable clinical research evidence to support the correlation of expression levels of these chemotherapy targets with patient responses to those drugs, there have been no prospective clinical trials to prove that they are indeed predictive of response in ovarian cancer. As a result, physicians are reluctant to use these tests as a basis for their decision making. But, in the 5 years that we have been providing profiling assistance, we have seen an increasing number of physicians who are using these results to inform their decisions. We are collecting patient results and outcomes in our database.

I would also like to mention that outside of chemotherapy drugs, there are drugs in clinical trials for ovarian cancer that may be better choices for some women.

The 200+ gene panel helps us provide information that can be used to identify such a clinical trial agent so that

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a clinical trial can be selected based on the patient’s tumor profile rather than choosing a trial just because it is at her doctor’s institution, which is how most doctors recommend clinical trials for their patients.

PMO How definitive or conclusive is the knowledge obtained from molecular profiling relevant to the diagnostic and the treatment process for patients with ovarian cancer?

Dr Shawver Each of the targets in the standard panel that Clearity tests for at our partner labs has considerable clinical evidence for its association with treatment benefit or lack thereof. These studies can be found on our Web site (www.clearityfoundation.org/health care-pros/drugs-and-biomarkers-staged.aspx). However, some of the evidence is for cancers other than ovarian.

This is one reason that Clearity is keeping a database and tracks women over time so that we can better establish the relevance of each of these tests. Ultimately, clinical trials will be needed, and the goal is to show preliminary evidence using our database that will establish the testing parameters for clinical trials. In contrast to the standard panel of tests, the evidence for drug responses for the markers tested in the 200+ gene panel is less robust because only some of them have been shown to be associated with drug response. We continually monitor the results reported for clinical trials so we can provide patients and physicians with the most up-todate, relevant information about the tests that may predict responses to drugs in clinical development.

PMO Is it more challenging to obtain genetic signatures in ovarian cancer than in other cancers?

Dr Shawver The actual laboratory testing is the same as for other cancers. One of the challenges, however, is in obtaining an appropriate specimen for testing. Dr Zajchowski and colleagues have shown that the results from a recent specimen are likely to be different from the primary tumor or an older specimen [Zajchowski et al. Mol Cancer Ther. 2012;11:492-502]. Therefore, we will not conduct the profiling on an archived tumor block unless it has been obtained within 1 year. Second surgeries for ovarian cancer are not common – although a recent study published at ASCO [http://meetinglib

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rary.asco.org/content/117950-132] provides support to do this – and while doctors are becoming more accepting of obtaining a tumor biopsy at the time of recurrence, it is sometimes too risky because of the tumor location.

PMO What strategy is Clearity following to raise the healthcare literacy of practicing oncologists and patients to accelerate the process of obtaining molecular profiles in ovarian cancer?

Dr Shawver The Clearity Foundation has been providing access to molecular profiling for 5 years. When we first started, it was very controversial, and we faced an uphill battle. However, because several recently approved drugs are associated with specific molecular alterations that identify patients who have a high likelihood of benefit from that agent, it is becoming standard practice in breast, lung, colon, and skin cancers to conduct molecular analyses. As a result, physicians are more likely to consider using a molecular profile to inform their treatment decisions. Thus, we have been helped in our mission to bring this approach to women battling ovarian cancer. Unfortunately, ovarian cancer patients are much more heterogeneous, and the number of tests that are needed to prioritize a treatment or a clinical trial is greater. This means a greater cost. Part of Clearity’s mission is to remove the cost argument for not conducting these tests. We get the word out in different ways – presenting our findings at the various oncology meetings, speaking with doctors and patients one-on-one, and providing educational forums.

PMO Does the founding of Clearity suggest that the cancer healthcare system alone is insufficient for meeting the special needs of ovarian cancer patients?

If so, what is primarily “missing” from the paradigm?

What fuels this oversight? And what is your remedy for correcting it?

Dr Shawver The numbers are just against us. Almost every woman diagnosed with epithelial ovarian cancer gets the same treatment, ie, a combination of a platinum (carboplatin or cisplatin) and a taxane (pac­ litaxel or docetaxel), following surgery to have her ovaries and uterus removed, along with anything else they

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Dr Shawver addresses the audience at a Clearity Foundation educational event. need to take out to optimally remove all the tumors.

Of the women diagnosed with stage III or stage IV cancer, which represents 75% of the diagnoses, 80% will get to remission where no tumor is detected. This is truly remarkable, so it is difficult to think about how to give a different agent when one has an 80% chance of a response. Here comes the other astounding fact: of the women who get into complete remission, 80% will recur, most in the first 2 years. So while the agents

Of the women diagnosed with stage III or stage IV cancer, which represents 75% of the diagnoses, 80% will get to remission where no tumor is detected. initially work and work very well, their effects are shortlived. However, even The Clearity Foundation cannot focus on how to find the 20% of women who will not respond to standard of care because it is hard to justify given the 80% complete response rate. Clearity helps women when standard of care does not work or when they recur following treatment – as most do. With the multiple drugs that are used to treat recurrent ovarian cancer, there is less than a 20% chance that the agent will work. Our remedy is to increase this really terri-

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ble statistic from less than 20% to something that gives both the woman battling this disease and the physicians treating it hope that she can have a cure the second time around.

Unfortunately, patients and doctors often do not approach us until they have had a second, third, or fourth recurrence. To give the best chance, we believe that every woman with recurrent ovarian cancer should be profiled on her first recurrence.

PMO Regarding translational medicine, how successfully do oncologists tend to apply research findings into practice?

Dr Shawver Translational medicine is not the focus of The Clearity Foundation. This is a very important aspect when developing a new drug. Clearity is focused on doing better with the drugs we already have by providing tests that can prioritize these treatments. Personalized, or precision, treatment is a better buzzword for what Clearity provides.

The more research that is carried out to elucidate the drivers of subsets of ovarian cancers, the more possible it will be to cure this disease.

PMO The obstacles to making translational medicine claims, it would seem, include the multitude of research studies, the incomplete scope of the process of care involved in treating any given disease state, and the reconciling of any study’s findings against the backdrop of NCCN [National Comprehensive Cancer Network] Guidelines and pathways. How well does the medical profession understand what it takes to distill research findings into clinical practice?

Dr Shawver I’m glad that you asked this question.

Most of what Clearity provides to physicians is a way to prioritize among the agents that are in the NCCN Guidelines for the treatment of recurrent ovarian cancer. These include the platinum agents, the taxanes, peg­ ylated liposomal doxorubicin, gemcitabine, topotecan,

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and pemetrexed. For the majority of patients, our tests prioritize only 1 of these agents. The usual agents that doctors prescribe for a first recurrence, either as a single agent or in combination with a platinum, are paclitaxel, pegylated liposomal doxorubicin, and gemcitabine. If there is less than a 20% chance that an agent will work, I don’t understand why everyone is not insisting on a test that can help prioritize. There is considerable clinical research evidence for each of the markers for these agents (which are posted on our Web site [www.clear ityfoundation.org/healthcare-pros/drugs-and-biomark ers-staged.aspx]) and the other 2 agents in the NCCN Guidelines that are less commonly used, topotecan and pemetrexed. For some drugs, good tests do not exist, and we need to acknowledge this as well. For example, there are not good markers for predicting responses to platinum. Therefore, we utilize more standard clinical determinants such as how long the patient was in remission following treatment with a platinum agent. If it is longer than 6 months, she would likely receive 1 of the drugs in combination with platinum rather than as a single agent.

PMO Is the practice of translational medicine in ovarian cancer research increasing, static, or being confused by the explosion of research data?

Dr Shawver Indeed, there is an explosion of research data. The findings of the recent comprehensive genomic analyses of ovarian cancer, exemplified by those from The Cancer Genome Atlas project, have helped classify ovarian cancers in ways that enable us to match new drugs in clinical trials to specific patients.

Without those results, the interest in ovarian cancer as an indication for some of these novel drugs would not be as high. The more research that is carried out to elucidate the drivers of subsets of ovarian cancers, the more possible it will be to cure this disease. The 200+ gene panel is used to identify those patients for whom these novel drugs may be the best choice.

PMO How closely or loosely aligned is translational medicine and NCCN Guidelines?

Dr Shawver Our core panel is designed to be exactly aligned to the best that it can be. As I mentioned be-

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fore, not all of the drugs have good tests where we rely on the clinical response data.

PMO How has your personal experience of surviving ovarian cancer changed your professional perspectives on translational research?

Dr Shawver As a scientist, translational research is finding ways to enrich patient populations for a response to a particular drug. Being a patient has made me much more focused on the urgency of this and on each individual as a real person with a family that cares if a drug works for them. I become impatient when I see drugs being developed for a population when it is well known that only a fraction will benefit. It makes me so mad. I think we should do better.

PMO What was the single most important unmet need you sought to fill when you founded Clearity?

Dr Shawver The standard paradigm for women who have recurrent ovarian cancer is to go from one chemotherapy to the next to the next and have a poor quality of life, and they ultimately succumb to their disease. Clearity was founded to change this paradigm and show that women with recurrent ovarian cancer can be cured. Cure is a big word, and we are often criticized for using it. However, as we frequently say, someone has to believe in a cure and help both patients who are fighting for their lives and doctors who have only seen incremental changes in this disease over the past 40 years.

PMO Since Clearity’s founding, has this need remained constant, or have priorities shifted?

Dr Shawver The need has remained constant. We have had anecdotal successes, but the key is to provide data that show what we do is working. Clearity is now focused on how to get more women with recurrent ovarian cancer and their doctors aligned with molecular profiling to prioritize their treatment choices so that not only can we continue to help on an individual basis, but we can provide the appropriate data.

PMO How closely aligned is Clearity’s mission to the growth of personalized medicine?

Dr Shawver Yes, this is what Clearity is focused on.

However, it is more difficult for ovarian cancer because we do not neatly fall into big buckets. For breast cancer,

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Several members of Clearity’s Board of Directors at the Someone Lived fund-raiser. there are 3 big buckets, and 2 of these buckets align to treatment choices that are associated with better outcomes. For ovarian cancer, we are still sorting this out, but we may need 100 buckets to do so.

PMO What effect is Clearity’s work having on healthcare disparities in ovarian cancer?

Dr Shawver We are proud that we have provided access to molecular profiling for women without health insurance. The tests are costly, however, and not all insurance companies reimburse the test, which puts

Being a patient has made me much more focused on the urgency of this and on each individual as a real person with a family that cares if a drug works for them. everyone, including Clearity, in a difficult situation.

If all insurance companies paid for the tests, we could focus our resources more on people without insurance.

PMO Clearity seeks to improve competency among several stakeholders through systems changes. I’d like to throw out several different stakeholders and get your insights as to what changes are needed within that group to improve ovarian cancer outcomes. To start, what can patients do?

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Dr Shawver Patients should insist on understanding why a drug is the right one for you. Educate yourself on the value of testing your tumor and be able to ask your doctor to provide these tests and explain the results.

PMO Researchers?

Dr Shawver Focus efforts on understanding how to select patients that will benefit from the new drugs being developed; don’t accept that a drug can get approved in an all-comers trial because it works in 20% to 30% of patients and therefore statistical significance can be obtained. This is negatively affecting the lives of 70% to 80% of people in your trials.

PMO Payers?

Dr Shawver Insist that your ovarian cancer patients have a Clearity test. Insist that the doctors follow up with us to provide follow-up data. We will provide you all of the data for analysis on cost-effectiveness.

PMO Medical associations?

Dr Shawver We need your help to collect the appropriate data. Encourage women to participate and ways to

validate profiling effort. Encourage cooperative efforts to place women in the most appropriate clinical trial.

PMO Pharma?

Dr Shawver Many of your drugs under development for other kinds of cancer will likely work in subsets of ovarian cancer. Create a consortium among companies so that patients can be funneled into each of your trials with only 1 centralized test. Clearity is willing to help by providing the tests to the consortium.

PMO What lessons does Clearity’s experience have for the rest of the cancer community?

Dr Shawver The Clearity model can be used as a template for other difficult-to-treat cancers. The types of tests are similar, often the same. We should all be collecting the appropriate data to prioritize treatment decisions, which provides actionable hope for people battling cancer.

PMO It was such a pleasure to speak with you. Your story is quite an inspiring one. Please accept our best wishes for continued success. u

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CONSIDERATIONS in

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ASK THE EXPERTS: Combination Versus Sequential Therapy 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 Rattanonont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

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 third issue, experts from the Winship Cancer Institute of Emory University answer questions related to the use of combination and sequential therapies for MM. 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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Ajay K. Nooka, MD, MPH, FACP Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Charise Gleason, MSN, ANP-BC, AOCNP Nurse Practitioner Winship Cancer Institute Emory University Atlanta, GA

Katherine Sanvidge Shah, PharmD, BCOP Hematology/Oncology Pharmacy Specialist Winship Cancer Institute Emory University Atlanta, GA

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM).

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 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 1.0 contact hour.

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 application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-016-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients

• Describe the pharmacokinetics and pharmacodynamics of novel agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens 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.

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Planners’ and Managers’ Disclosures William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Bobbie Perrin, RN, OCN, MLI Reviewer, has nothing to disclose.

Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Sagar Lonial, MD, is on the Advisory Board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices.

Ajay K. Nooka, MD, MPH, FACP, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use for any products/devices.

Charise Gleason, MSN, ANP-BC, AOCNP, is a consultant for Celgene Corporation. She does intend to discuss either non–FDAapproved or investigational use for the following products/devices: agents currently used in clinical trials for MM. Katherine Sanvidge Shah, PharmD, BCOP, has nothing to disclose. She does intend to discuss either non–FDA-approved or in-

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Understanding Combination and Sequential Therapy in Multiple Myeloma Ajay K. Nooka, MD, MPH, FACP

Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine, Atlanta, GA

Introduction Over the past decade, an increased knowledge of multiple myeloma (MM) and of the physiologic factors affecting its growth and proliferation have led to the development and approval of numerous targeted agents, including bortezomib, thalidomide, lenalidomide, carfilzomib, and pomalidomide. Given the expanding treatment armamentarium for the disease, physicians are often faced with the question of whether to offer patients combination or sequential therapy. In this article, Ajay K. Nooka, MD, MPH, FACP, discusses this issue in the context of the latest data from clinical trials, and provides insights on practices that contribute to optimal patient care.

What are the advantages and disadvantages of sequential versus combination therapy in MM? The term sequential therapy refers to treatment with drug regimens administered one after another in a chronological fashion rather than concomitantly,

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while the term combination therapy alludes to more than one drug treatment administered concurrently. The best example of combination therapy in the era of modern antimyeloma treatment originates from combining a proteasome inhibitor (PI) with an immunomodulatory drug (IMiD). The PI bortezomib combined with the IMiD lenalidomide exhibited synergy in preclinical models, and newly diagnosed patients in a phase 1/2 trial achieved high overall response rates (ORRs) of 100% with greater than one-third of patients achieving a complete response (CR)/near-complete response.1 These results are not limited to the induction setting. For example, consolidation with bortezomib/thalidomide/ dexamethasone (VTD) following autologous stem cell transplantation (ASCT) has induced molecular responses by upgrading the quantitative polymerase chain reaction (qPCR)-positivity to qPCR-negativity, suggesting that combination therapies may be able to deliver molecular responses, where conventional agents failed to achieve similar responses.2 Sequential therapy can be interpreted in more than one way. First, it can mean sequential administration of therapies, switching to a new regimen following disease progression. Second, it can mean a predefined sequence of therapies, each new regimen following the previous therapy without evidence of disease progression. The best example in recent myeloma literature is that of a phase 2 feasibility study in which sequential bortezomib and dexamethasone (VD) for 6 cycles, followed by thalidomide and dexamethasone (TD) maintenance therapy until progression following ASCT, demonstrated that a prolonged sequential weekly regimen is feasible and well tolerated, with post-ASCT CR upgraded by more than one-third during maintenance therapy, with no further increase in grade 3/4 peripheral neuropathy (PN).3

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CONTINUING EDUCATION The underlying concept of sequential therapy arises from the idea of preserving therapeutic options for later use in the disease course. Another potential advantage of sequential therapy is to limit the toxicities associated with combination therapies. This notion presumes that curing the disease is not the primary goal, and that progression-free survival (PFS) as well as overall survival (OS) are equivalent with both sequential and combination therapies. This argument is largely supported by data from historical ineffective combinations of chemotherapy when compared with a standard melphalan and prednisone (MP) regimen. Due to the low ORR for any of these historical regimens, it is not surprising that the use of sequential therapy was as ineffective as combination therapy.

However, with the use of newer, more active agents such as IMiDs and PIs, as well as a better understanding of the biology of the disease, reconsideration of sequential therapy is warranted.

Combination approaches with currently available highly effective regimens are more effective at inducing durable responses than sequential single agents.

The rationale seems logical: myeloma cells follow Gompertzian rather than exponential kinetics, which forms the basis for ASCT, suggesting enhanced susceptibility to combination therapies with the goal of minimizing residual tumor burden and deepening the response. In addition, combination therapies have allowed for targeting induced-pathway dependence. The exposure of malignant cells to a single agent often results in preferential overactivation of a survival pathway that can be targeted by using the second agent as part of a combination strategy. Also, combination therapies can lead to synergistic mechanisms of tumor apoptosis, allowing for better overall response and depth of response when compared with single-agent therapy. This notion presumes that achieving depth of response with a safe and tolerable durable therapy actually results in survival improvement. The downside to this approach is the lack of long-term data confirming that combination therapies provide a survival advantage over singleagent therapy. However, with a better understanding of clonal dynamics and recent description of “clonal tides,” along with evidence of the existence of clonal heterogeneity at diagnosis, the argument is in favor of combination therapies over sequential therapies, especially when the intent is to eradicate both the dominant and minor clones that emerge at relapse.4 Which factors can affect the order of agents used in a sequential approach to therapy?

In the current fast-paced era of antimyeloma therapies, with practices rapidly adapting to novel combination treatment strategies, it may not be feasible to conduct a study randomizing to sequential or combination therapies with a primary end point of OS, especially when data suggest that improved depth of response translates to PFS and OS advantage. A retrospective outcomes analysis evaluated whether the sequence of treating with lenalidomide-based therapy followed by bortezomib-based therapy versus bortezomib-based therapy followed by lenalidomide-based therapy improved outcomes. This study included 208 patients and reported that sequence of therapy was not predictive of OS, except in patients with renal failure, where bortezomib-based first-line therapy was recommended.5 In another study, the Myeloma Research Council XI randomized patients receiving cyclophosphamide/thalidomide/dexamethasone (CTD) or cyclophosphamide/lenalidomide/dexamethasone (CRD) who had not achieved at least a partial response to receive either no further therapy or a triplet combination of cyclophosphamide/bortezomib/dexamethasone (CVD). A mean paraprotein reduction of 74% from the start of CVD was observed, suggesting that a bortezomib-based combination therapy would have delivered these responses at the start.6 These results were confirmed in a meta-analysis of phase 3 trials of bortezomib-based induction therapies, suggesting that the addition of bortezomib to the induction regimen not only improved response rates but also resulted in prolonged PFS and OS.7 Similar data in transplant-ineligible patients were reported in the phase 3 VISTA trial.8 OS was prolonged with the combination of bortezomib/melphalan/prednisone (VMP) compared with patients who received first-line MP followed by salvage bortezomib, suggesting a survival advantage with combination therapies. OS from start of subsequent therapy was similar following the VMP and MP regimens, suggesting that combination therapies do not induce more resistant relapses.9 These observations add strength to the argument that combination therapies—especially those including bortezomib in the induction setting—improve response rates and further outcomes.

As myeloma is mainly a disease of elderly patients, with a median age at diagnosis of 69 years,8 approximately 50% of patients are not transplant eligible at

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the time of diagnosis. Also, due to the prevalence of MM in the elderly, it is not uncommon to encounter patients who are frail, exhibit poor functional status, and have multiple comorbidities. These patients are more susceptible to treatment-related adverse events, may have lower tolerability for full drug doses, and may be on other medications that interact with their antimyeloma treatment.

The question of whether these patients can tolerate combination therapies is always challenging. Taking age into consideration, beneficial results of the VISTA trial demonstrated a median survival advantage of 13 months with combination therapies.9 Taking frailty into consideration, a gentler approach of combination therapies with lower intensity dosage regimens improves the safety profile and thus optimizes treatment outcomes. A plan for further reduction in dosages is recommended with close monitoring.10 One of the most notable concepts to which the myeloma community has quickly adapted in recent years is the recognition of risk stratification, spanning from the most indolent to the most aggressive forms on the MM spectrum. The majority of myeloma-treating physicians accept genetically defined risk stratification and the fact that high-risk patients have poorer survival outcomes compared with other patients with MM. At the least, combination therapies, preferably including an IMiD and a PI, are agreed upon as best for induction in this high-risk patient group. Early genomic data support this approach of targeting all coexisting disease subclones with aggressive combination therapies and avoiding sequential single-agent therapy in high-risk patients.4 Moreover, data also suggest that by using sequential therapy early in the disease course, early suboptimal treatment of myeloma may sometimes preferentially eradicate the more indolent clone, thus leaving room for expansion of the aggressive clone.4 A similar rationale supports combination therapies in the maintenance setting in high-risk patients; early clinical data concur with these findings.11 What are the latest data regarding the safety and efficacy of combination regimens in MM? In newly diagnosed myeloma patients, triplet regimens have been proven to be highly effective in delivering high-quality durable responses with a satisfactory toxicity profile. The combinations of IMiDs and a PI demonstrated synergy as previously described and resulted in quality responses.1 With the use of next-generation PIs and IMiDs, much deeper response rates have been observed.

Moving a step further, combinations of newer monoclonal antibodies and histone deacetylase inhibitors have the potential to augment the quality of responses and translate into improved PFS and OS. Figure 1 illustrates the upgraded responses achieved with doublets to triplets with various combinations of newer agents and signifies the importance of combination therapies.1,12-16 In contrast to the robust evidence supporting the advantages of treating newly diagnosed patients with combination therapies, using a similar approach when treating patients with relapsed/refractory MM has proven more challenging.

Often these patients have already been treated with multiple agents and may have more comorbidities secondary to the disease itself or due to prior treatment-related effects. Salvage regimens used in this setting previously resulted in inadequate responses and shorter duration of response, as shown in Figure 2.17-28 However, the addition of liposomal doxorubicin to bortezomib prolonged median PFS to 9.3 months among bortezomib-naive patients versus 6.5 months for bortezomib alone, showing the value of a combination approach.23 More recently, a phase 3 trial in the relapsed setting comparing VTD with TD reported PFS of 19 months for the VTD arm, representing the longest PFS in a relapsed setting and highlighting the importance of combination therapy.28 Various methods have been utilized to address the issue of overlapping toxicity with combination therapy (eg, increased grade 3 PN): dose or schedule modification of the agents, route of administration of bortezomib, newer IMiDs to decrease PN, and newer PIs such as carfilzomib and oprozomib are potential options.

However, the key principle of combination therapy yielding effective reduction of disease burden and improving PFS will guide us in defining future studies.

The role of quadruplet therapies remains unclear at this time. In both transplant-eligible and -ineligible populations, regimens such as lenalidomide/bortezomib/cyclophosphamide/dexamethasone (RVCD), bortezomib/cyclophosphamide/ thalidomide/dexamethasone (VCTD), lenalidomide/bortezomib/doxorubicin/ dexamethasone (RVDD), and bortezomib/melphalan/prednisone/thalidomide (VMPT) have been evaluated, with outcomes similar to triplet therapies, albeit with higher toxicities. With appropriate dosage modifications to reduce the risk of toxicity, these regimens can be administered in some patients, if the objective is to

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Figure 2. Upgraded responses observed with doublets to triplets in combination therapy for patients with relapsed/ refractory myeloma.17-28

CR/nCR indicates complete response/near-complete response; C, cyclophosphamide; D, dexamethasone; PR, partial response; R, lenalidomide; T, thalidomide; V, bortezomib; VGPR, very good partial response.

achieve greater depth of response, demonstrated as higher molecular remissions.

Rather than using the historically ineffective alkylator-based therapy in these combination regimens, investigational biological agents hold promise. ♦ References

1. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686.

2. Cavo M, Pantani L, Petrucci MT, et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012;120:9-19.

3. Sahebi F, Frankel PH, Farol L, et al. Sequential bortezomib, dexamethasone, and thalidomide maintenance therapy after single autologous peripheral stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant. 2012;18:486-492.

4. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012;120:1067-1076.

5. Patel AM, Ho VQ, Shain KH, et al. Sequence of therapy in multiple myeloma: does it matter?: retrospective evaluation of patients with multiple myeloma who have received bortezomib followed by lenalidomide or vice versa. Blood (ASH Annual Meeting Abstracts). 2011;118: Abstract 3979.

6. Pawlyn C, Davies FE, Gregory WM, et al. Sequential immunomodulatory drug (IMiD) and proteosome inhibitor therapy improves response rates in newly diagnosed multiple myeloma: preliminary results from the Myeloma XI trial. Blood (ASH Annual Meeting Abstracts).

2012;120:Abstract 335.

7. Nooka AK, Kaufman JL, Behera M, et al. The improved efficacy of bortezomib containing induction regimens (BCIR) versus non-bortezomib containing induction regimens (NBCIR) in transplant-eligible patients with multiple myeloma (MM): meta-analysis of phase III randomized controlled trials (RCTs). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3994.

8. San Miguel JF, Schlag R, Khuageva NK, et al; for the VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917.

9. San Miguel JF, Schlag R, Khuageva NK, et al. Continued overall survival benefit after 5 years’ follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: final results of the phase 3 VISTA trial. Blood (ASH Annual Meeting Abstracts).

2011;118:Abstract 476.

10. Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood.

2011;118:4519-4529.

11. Kaufman JL, Nooka AK, Muppidi S, et al. Survival outcomes of early autologous stem cell transplant (ASCT) followed by lenalidomide, bortezomib, and dexamethasone (RVD) maintenance in patients with high-risk multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Proceedings). 2012;30(15 suppl):Abstract 8100.

12. Harousseau J-L, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629.

13. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolida-

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Figure 1. Upgraded responses observed with doublets to triplets in combination therapy for patients with newly diagnosed myeloma.1,12-16

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tion therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.

14. Rajkumar SV, Jacobus S, Callander NS, et al; for the Eastern Cooperative Oncology Group.

Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37.

15. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma.

Blood. 2012;120:1801-1809.

16. Kaufman JL, Shah JJ, Laubach JP, et al. Lenalidomide, bortezomib, and dexamethasone (RVD) in combination with vorinostat as front-line therapy for patients with multiple myeloma (MM): results of a phase 1 study. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 336.

17. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565-1571.

18. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood.

2002;100:3063-3067.

19. Richardson PG, Sonneveld P, Schuster MW, et al; for the Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498.

20. Dimopoulos MA, Zervas K, Kouvatseas G, et al. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001;12:991-995.

21. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142.

22. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004;127:165-172.

23. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25:3892-3901.

24. Richardson PG, Alsina M, Weber DM, et al. Phase II study of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory multiple myeloma (PANORAMA 2). Blood (ASH Annual Meeting Abstracts).

2011;118:Abstract 814.

25. Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II trial of lenalidomide, bortezomib, and dexamethasone in patients (pts) with relapsed and relapsed/refractory multiple myeloma (MM): updated efficacy and safety data after >2 years of follow-up. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 3049.

26. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophosphamide, Velcade and dexamethasone (CVD) induces high response rates with comparable toxicity to Velcade alone (V) and Velcade plus dexamethasone (VD). Haematologica. 2007;92: 1149-1150.

27. Lonial S, Jakubowiak AJ, Jagannath S, et al. A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 303.

28. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30: 2475-2482.

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Nursing Considerations for Combination Therapy in Multiple Myeloma Charise Gleason, MSN, ANP-BC, AOCNP Nurse Practitioner Winship Cancer Institute Emory University, Atlanta, GA

Introduction Although there has been significant clinical benefit seen with newer regimens for multiple myeloma (MM), challenges remain, including the occurrence of adverse events (AEs). As a member of the cancer care team, it is the nurse’s responsibility to anticipate which toxicities and complications are likely to occur with treatment, to employ the necessary interventions, and to counsel patients accordingly. In this article, Charise Gleason, MSN, ANP-BC, AOCNP, discusses effective nursing strategies in the setting of combination antimyeloma therapy, and shares her perspectives on preventing and managing side effects related to the use of specific novel agents.

What are some of the effective supportive care strategies that can be used for controlling AEs associated with frontline combination regimens in transplant-eligible patients?

Management of MM has changed dramatically with the introduction of newer therapies.1 There are currently several frontline regimens available for the treatment of transplant-eligible patients, as outlined in the latest guidelines from the National Comprehensive Cancer Network.2 Common induction regimens include bortezomib, thalidomide, and dexamethasone (VTD), lenalidomide, bortezomib, and dexamethasone (RVD), bortezomib plus dexamethasone (VD), and cyclophosphamide, bortezomib, and dexamethasone (CyBorD).2 Treatment for symptomatic myeloma is first stratified based on transplant eligibility.

Clinical considerations when choosing an induction regimen include tumor burden, hypercalcemia, renal status, cytogenetic abnormalities, performance status, and preexisting comorbidities.2-4 During induction, patients may develop treatment-related toxicities such as peripheral neuropathy (PN), infection, gastrointestinal (GI) toxicities, and thrombosis (deep vein thrombosis/pulmonary embolism [DVT/PE]), all of which require careful monitoring and effective management strategies.

Peripheral Neuropathy Neuropathy remains a major challenge in the treatment of patients with MM. The nursing implications related to this toxicity are far-reaching and encompass patient education, frequent monitoring of symptoms, and participation in multidisciplinary decisions to adjust drug dose or schedule, and in some cases, to interrupt or discontinue treatment.

Obtaining an accurate assessment of PN at baseline is critical to patient follow-up. After baseline evaluation, close monitoring at each visit promotes early detection.5 Patient education is actually an important component of this process, since a well-informed patient knows what signs and symptoms to report to the cancer care team.

Nurses must distinguish between neuropathy related to the myeloma disease process and neuropathy that is related to treatment.5 Myeloma-related PN is mainly sensory or sensorimotor; typical symptoms include paresthesias, hyperesthesias, numbness, and tingling that typically start distally and move proximally.5-8 Treatment-related PN, on the other hand, is typically symmetrical, distal, and progressive, and symptoms may vary depending on the agent being administered.5,9-15 For example, the 2 antimyeloma agents most commonly associated with PN—bortezomib and thalidomide—have different PN symptom profiles.

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Bortezomib-induced PN is predominantly sensory and mild, although up to 15% of patients report severe sensory and motor PN.5 Symptoms of bortezomib-induced PN include burning, hyperesthesia, hypoesthesia, paresthesia, discomfort, numbness, pain, and weakness.5,12,13 In contrast, thalidomide-induced PN may be permanent, and symptoms may even occur after the cessation of therapy.5,9,10 PN associated with thalidomide tends to be sensory/sensorimotor neuropathy, with tingling or painful distal paresthesia affecting the feet or hands, with a loss of sensation in the lower limbs.5 Muscle weakness or tremor may also occur.5 Both bortezomib and thalidomide have been associated with lower-extremity weakness, although this symptom is more commonly seen with thalidomide use.14,15 Bortezomib has traditionally been administered by the intravenous (IV) route, but recent data suggest that the subcutaneous (SC) route may help to minimize PN in bortezomib-treated patients.15,16 SC administration of bortezomib is comparable to IV administration in systemic availability and response rates.15,16 A randomized trial by Moreau and colleagues reported a reduction in bortezomib-induced PN with the SC route, from 53% to 38% for all grades of PN, and from 16% to 6% in grade 3 /4 PN. At our center, we are now using SC bortezomib in our induction regimens and have found a significant decrease in patient chair time.

Pharmacologic treatment of PN includes the use of pregabalin, gabapentin, tricyclic antidepressants, opioids, duloxetine, and topical interventions such as local lidocaine patches, cocoa butter, or menthol ointment.17,18 Duloxetine is the first drug to be evaluated in a randomized trial to treat painful chemotherapy-induced PN. In this trial (N=231),19 Smith and colleagues observed that 5 weeks of duloxetine treatment decreased pain severity compared with placebo among patients with grade ≥1 sensory neuropathy.

When documenting PN, nurses can grade severity via National Cancer Institute (NCI) toxicity criteria for neuropathy.20 These criteria are listed for peripheral motor and peripheral sensory neuropathy and are available at http://ctep. cancer.gov. Grading ranges from grade 1 (asymptomatic neuropathy with clinical observation of some deficits) to severe, symptomatic neuropathies of grade ≥3.

Infection Patients with MM are at an increased risk for infection, which is the leading cause of death in this patient population.21 Any treatment that produces myelosuppression—including lenalidomide, cyclophosphomide, dexamethasone, and bortezomib—can further increase the risk of opportunistic infections. Patients need to be educated on the importance of infection control practices such as good general hygiene, hand washing, oral care, and central line maintenance.

Prompt reporting of symptoms and appropriate treatment are essential to avoid severe infections and treatment interruption.

Herpes zoster reactivation has been reported with bortezomib-containing regimens.22,23 Therefore, prophylaxis with an antiviral agent (eg, acyclovir) is important in regimens containing bortezomib and is effective in reducing the risk for zoster reactivation. The herpes zoster vaccination is not recommended, although patients should receive the pneumococcal and influenza vaccines.24 The use of IV immunoglobulin may help with recurrent infections, although no randomized trials support this practice.

Gastrointestinal Toxicities GI toxicities such as nausea and vomiting, diarrhea, and constipation can occur with numerous antimyeloma therapies, including lenalidomide, thalidomide, and bortezomib.25 In the transplant-eligible patient who receives melphalan for conditioning in autologous stem cell transplantation, these AEs can be very severe and may lead to life-threatening GI mucositis.26 Toxicities such as these have a marked impact on quality of life and may lead to poor adherence to therapy, loss of appetite, decreased function, anxiety, and social isolation.25 The International Myeloma Foundation Nurse Leadership Board recommends routine assessment and active intervention to manage the GI effects of

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lenalidomide, thalidomide, and bortezomib.25 Recommended assessment methodology applies NCI grading criteria to findings from history-taking, symptom self-report, examination, and laboratory testing for electrolytes and other chemistries.25 Assessment should always include an evaluation of patient-related factors that may predispose individuals to GI effects, as these may lead to exacerbation of symptoms during antimyeloma therapy. These include age (eg, >65 years for constipation and diarrhea, but <50 years for nausea) and improper diet (eg, low fiber intake for constipation), as well as additional medications, comorbidities, and surgical/medical procedures (eg, radiation therapy for emesis).25 At the outset of therapy, it is important for nurses to educate patients and caregivers on the risk for GI toxicities and on the importance of good hydration, a diet with sufficient fiber, and the basics of proper nutrition. When a GI event occurs, education on appropriate interventions such as the use of antiemetics, laxatives, or antidiarrheals should be provided, and reinforced as needed. Patients may need robust support from nurses to help them cope with the physical and psychosocial effects of these AEs and to adhere to bowel regimens and other protocols.

Venous Thromboembolic Events Thrombosis is a complication observed with certain malignancies and their treatment, and it is especially common in myeloma, which may be associated with a “background” incidence of venous thromboembolic events of 5% to 10%.27,28 The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide further elevate the risk of thrombosis.27-29 A review of select studies that were conducted without mandated antithrombotic prophylaxis suggests that the risk of thrombosis with thalidomide plus dexamethasone ranges from 12% to 15%— about 4 to 5 times higher than with single-agent dexamethasone.27 Similar results have been seen with lenalidomide and dexamethasone.27 Individual risk factors, quite apart from MM or antimyeloma therapy, may add substantially to patients’ risk. These additional factors include older age, previous DVT/PE, immobilization, trauma, central venous catheter, surgery, and some medications (eg, erythropoietin).28-30 Moreover, certain drugs in combination with an IMiD elevate risk; notable among these are high-dose dexamethasone and doxorubicin.30 Antithrombotic prophylaxis is generally recommended for patients receiving therapy that includes an IMiD. The current recommendation for patients with low (0-1) additional risk factors is aspirin 81 mg to 325 mg once daily; when a patient has high (≥2) additional risk factors, recommended prophylaxis is either low-molecular-weight heparin (enoxaparin 40 mg/day or its equivalent) or warfarin to an international normalized ratio of 2 to 3.30 What are some common toxicities associated with newer agents being used in the relapsed/refractory setting?

At our center, we treat patients experiencing relapsed/refractory disease with several novel agents, including carfilzomib and pomalidomide. It is imperative that nurses become familiar with the toxicity profiles of these and other therapies being utilized in this setting for MM. Carfilzomib is a next-generation IV proteasome inhibitor,31 approved by the US Food and Drug Administration (FDA) for relapsed and/or refractory MM. In pivotal clinical trials, the most common AEs of all grades reported with this agent include fatigue (55.5%), anemia (46.8%), nausea (44.9%), thrombocytopenia (36.3%), dyspnea (34.6%), diarrhea (32.7%), and pyrexia (30.4%).32 Carfilzomib is associated with a lower incidence of severe PN than thalidomide or the other available proteasome inhibitor, bortezomib; incidence of grade 3 PN was 1% in clinical trials.32 Nurses who administer carfilzomib must be alert to rare but potentially serious infusion reactions and tumor lysis syndrome.32 To ward off these problems, slower infusion (eg, over ≥10 minutes), prehydration, and optional posthydration fluids, and pretreatment steroid prophylaxis are recommended approaches.

Pomalidomide is a next-generation oral immunomodulatory agent that has been approved by the FDA for the treatment of relapsed and refractory MM. Pomalidomide in combination with low-dose dexamethasone has demonstrated clinical activity in patients following relapse after multiple lines of therapy, including patients who are refractory to lenalidomide and bortezomib.33-36 Common AEs reported in pivotal trials with single-agent pomalidomide include fatigue/asthenia (55%), neutropenia (52%), anemia (38%), constipation

(36%), nausea (36%), diarrhea (34%), dyspnea (34%), upper respiratory tract infection (32%), and back pain (32%).37 The risk for PN is lower with this agent than with thalidomide; the incidence of neuropathy was 10% in pivotal trials with single-agent pomalidomide.

Data from a recent phase 1/2 trial showed comparable AEs with pomalidomide alone (POM) or in combination with low-dose dexamethasone (POM+LoDex).36 Discontinuations due to AEs were 7% and 12% for the 2 treatment groups, respectively. Incidence rates of PN, DVT, and renal failure reported with POM compared with POM+LoDex, respectively, were as follows: 7% vs 10%, 2% vs 1%, and 2% vs 1%.

Pomalidomide should be taken without food and given at least 2 hours before/ after meals.37 Nurses should educate patients and caregivers on antithrombotic prophylaxis, infection risk, fatigue, and the importance of adhering to a consistent schedule. ♦ References

1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.

2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. V2.2013. http://www.nccn.org. Accessed June 2, 2013.

3. Stadtmauer EA. Tailoring initial treatment for newly diagnosed, transplantation-eligible multiple myeloma. Oncology. 2010;24(suppl 2):7-13.

4. Niesvizky R, Coleman M, Mark T. Best practices in the management of newly diagnosed multiple myeloma patients who will not undergo transplant. Oncology. 2010;24(suppl 2):14-21.

5. Richardson PG, Delforge M, Beksac M, et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia. 2012;26:595-608.

6. Kyle RA. Monoclonal proteins in neuropathy. Neurol Clin. 1992;10:713-734.

7. Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med. 1998;338:1601-1607.

8. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008;111:3968-3977.

9. Mothy B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica. 2010;95: 311-319.

10. Thalomid [package insert]. Summit, NJ: Celgene Corporation; February 2013.

11. San Miguel JF, Richardson PG, Orlowski RZ, et al. Risk of second primary malignancies (SPMs) following bortezomib (Btz)-based therapy: analysis of four phase 3 randomized controlled trials in previously untreated or relapsed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 2933.

12. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib.

J Clin Oncol. 2006;24:3113-3120.

13. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-2498.

14. Sonneveld P, Jongen JLM. Dealing with neuropathy in plasma-cell dyscrasias. Hematology (ASH Education Program Book). 2010:423-430.

15. Berkowitz A, Walker S. Bortezomib-induced peripheral neuropathy in patients with multiple myeloma. Clin J Oncol Nurs. 2012;16:86-89.

16. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

17. Tariman J, Love G, McCullagh E, et al. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board.

Clin J Oncol Nurs. 2008;12(suppl):29-35.

18. Delforge M, Bladé J, Dimopoulos MA, et al. Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol. 2010;11:1086-1095.

19. Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013;309:1359-1367.

20. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE), v4.03. http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/ctc.htm. Accessed August 7, 2013.

21. Ludwig H, Zojer N. Supportive care in multiple myeloma. Best Pract Res Clin Haematol. 2007; 20:817-835.

22. Kim SJ, Kim K, Kim BS, et al. Bortezomib and the increased incidence of herpes zoster in patients with multiple myeloma. Clin Lymphoma Myeloma. 2008;8:237-240.

23. Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. 2008;26:4784-4790.

24. Wood SK, Payne JK. Cancer-related infections. J Adv Pract Oncol. 2011;2:356-371.

25. Smith LB, Bertolotti P, Curran K, et al. Gastrointestinal side effects associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12:37-51.

26. Sharma SK, Handoo A, Choudhary D, Dhamija G, Gupta N. Severe gastrointestinal mucositis following high dose melphalan therapy for multiple myeloma. World J Gastroenterol.

2013;19:784-785.

27. Zonder JA. Thrombotic complications of myeloma therapy. Hematology (ASH Education Program Book). 2006:348-355.

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Pharmacologic Considerations in the Era of Novel Therapies for Multiple Myeloma Katherine Sanvidge Shah, PharmD, BCOP Hematology/Oncology Pharmacy Specialist Winship Cancer Institute Emory University, Atlanta, GA

Introduction The development of more effective drugs has led to better response rates and prolonged survival in multiple myeloma (MM). When choosing among these therapies, it is essential to consider factors such as pharmacologic profiles and drug–drug interactions to ensure optimal patient outcomes. In this article, Katherine Sanvidge Shah, PharmD, BCOP, discusses new directions in antimyeloma treatment and provides insight into the mechanism of action of both approved and investigational agents being used in combination and sequential therapies.

What are some of the drug–drug and drug–dietary interactions that may occur with commonly used agents for MM? When patients are treated with the proteasome inhibitor (PI), bortezomib, it is important to counsel them on possible dietary modifications they may need to make. In vitro and in vivo data suggest that several components of green tea and green tea extract can antagonize the antimyeloma effectiveness of this agent.1 In MM cell lines, epigallocatechin gallate and several other polyphenols have interfered with the proteasome-inhibiting actions of bortezomib and prevented tumor cell death.2 Patients should be instructed to avoid consuming green tea and its extract while receiving concomitant bortezomib. Ascorbic acid or vitamin C is another supplement of concern.3 Studies have shown that vitamin C can inhibit the activity of bortezomib through direct binding between the hydroxyl group of the antioxidant agent and the boronic acid of the PI. This binding decreases the affinity of the PI for the chymotrypsin-like subunit of the proteasome, thus decreasing the anticancer effect.4 This was confirmed in a study by Perrone and colleagues, which showed that a dose-dependent effect of ascorbic acid decreased the effectiveness of bortezomib.5 It is recommended that patients do not exceed 500 mg of ascorbic acid a day and that they separate administration by at least 12 hours before or after bortezomib administration, given the fact that the half-life of oral ascorbic acid is 10 hours.5 In general, it is probably best to instruct patients to avoid extra vitamin C supplementation and vitamin C–containing multivitamins during bortezomib therapy. St. John’s wort (hypericum perforatum) should also be avoided, since it has the potential to induce the cytochrome P450 34A enzyme system and therefore decrease bortezomib plasma concentrations.6 A drug–drug interaction that is unavoidable due to the therapeutic efficacy of the regimen is the one that occurs when the immunomodulatory drug (IMiD) lenalidomide is combined with dexamethasone. The concern with this regimen is the significantly increased risk of thromboembolism. In 2 studies of patients with relapsed or refractory MM, the incidence of grade 3/4 venous thromboembolic events (VTEs) was significantly higher when these agents were used together than when dexamethasone was administered alone (11.4%-14.7% vs 3.4%4.6%, respectively).7,8 Currently, it appears the best options for VTE prophylaxis with this combination are low-molecular-weight heparin or warfarin (with a targeted international normalized ratio of 2-3), especially in cases in which highdose dexamethasone is prescribed.9 Aspirin is another option for VTE prophylaxis, particularly when low-dose dexamethasone is utilized.10 Of course, it is also essential to educate patients on the signs and symptoms of VTE, such as erythematous, warm, swollen, or painful extremities for deep vein thrombosis, and shortness of breath, pain upon inspiration, and cough for pulmonary embolism.10

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Can you discuss how next-generation agents may help to improve outcomes in MM? Several new agents are allowing for extended, durable responses and disease control, which are allowing patients with MM to live longer. PIs have been proven to be one of the major milestones in the MM treatment landscape, leading to improved outcomes in the frontline as well as relapsed/refractory settings.

Carfilzomib, a next-generation PI, differs from bortezomib in that it exhibits irreversible and sustained inhibition on the proteasome, is more potent, and is more selective in its action, which may translate to fewer side effects such as neuropathy.11 On July 20, 2012, the US Food and Drug Administration granted accelerated approval to carfilzomib for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an IMiD, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. Approval was based on results of the open-label, single-arm phase 2b study, PX-171-003-A1. The overall response rate (ORR) was 22.9%, with a duration of response of 7.8 months.11 Although carfilzomib is currently approved at a standard dose of 27 mg/m2 infused over 2 to 10 minutes, it is being investigated at higher doses with a prolonged infusion time of 30 minutes to prevent infusion-related reactions.

Due to the projected shortage of oncologists/nurses and the potential for decreased availability of infusion sites, increased efforts into the safety and efficacy of oral chemotherapeutic options is essential. Fortunately, there are several orally bioavailable PIs currently under investigation.

MLN9708 (ixazomib), an orally available, second-generation PI, is a dipeptidyl boronic acid that is rapidly hydrolyzed in water and converts into MLN2238, the active form which potently, reversibly, and selectively inhibits the proteasome, primarily binding to the β5 subunit of the 20S proteasome.

MLN9708 exhibits a shorter proteasome dissociation half-life (18 minutes vs 110 minutes), a larger volume of distribution, and increased pharmacodynamic effects in tissues compared with bortezomib.12 This agent is the first oral PI to enter clinical trials, and it is currently being evaluated in both once-weekly and biweekly schedules in the relapsed/refractory setting.13-15 In addition, the upcoming phase 3, randomized, double-blind, multicenter, TOURMALINEMM2 trial will compare MLN9708 plus lenalidomide and dexamethasone with placebo plus lenalidomide and dexamethasone in nontransplant patients with newly diagnosed MM. Another orally available PI currently under investigation is ONX-0912 (oprozomib), a structural analog of carfilzomib that is currently being investigated in phase 1 and 2 trials (See Table).16 Pomalidomide is a novel, third-generation IMiD, with immunomodulatory, antiangiogenic, and direct antimyeloma activity. Created by chemical modifications to the structural backbone of thalidomide, pomalidomide exhibits more potent anti-inflammatory activity and appears to demonstrate a more favorable toxicity profile.17 This has translated into clinical efficacy even in heavily pretreated patients.

For example, Jagannath and colleagues recently reported on results of a multicenter, randomized, open-label phase 2 study (MM-002) evaluating the safety and efficacy of pomalidomide (POM) alone or in combination with low-dose dexamethasone (POM+LoDEX) in 221 patients with relapsed and refractory MM who have received multiple prior therapies, including lenalidomide and bortezomib.18 ORRs were 34% in the POM+LoDEX group and 15% in the POM alone group. The median duration of response (for patients who achieved ≥PR) was 45 months in the POM+LoDEX group and 31 months in the POM group. Results of a subanalysis based on age (≥65 years vs <65 years) showed that age had no impact on the duration or depth of response. The median progression-free survival for the overall population was 4.6 months for those who received POM+LoDEX and 2.6 months for those who received POM.

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Table. Next-generation Oral Proteasome Inhibitors for MM16

or improvement to PR. Grade 3/4 AEs included thrombocytopenia (64%) and peripheral neuropathy (8%).23 ♦

Proteasome Inhibitor

References

MLN9708

Type

Pattern of Inhibition

Clinical Trial Investigation

Adverse Events

Boronic acid

Reversible

Phase 1, 2,

Fatigue,

and 3

thrombocytopenia, N/V, diarrhea

Phase 1 and 2

N/V, diarrhea, abdominal pain, fatigue, decreased appetite

(ixazomib) ONX-0912 (oprozomib)

Epoxyketone

Irreversible

MM indicates multiple myeloma; N/V, nausea/vomiting.

What investigational histone deacetylase inhibitors are showing promise in MM? Histone deacetylase (HDAC) inhibitors promote the acetylation of histone proteins, thereby decondensing chromatin to its active form and reversing epigenetic silencing of transcription factors and tumor suppressor genes which regulate cell growth. HDAC inhibitors have been shown to inhibit proliferation and induce apoptosis in MM cell lines. Although HDAC inhibitors have failed to improve outcomes when used as single agents, they appear to be synergistic both in vitro and in vivo when combined with other anti-MM agents, particularly PIs. The molecular basis underlying this synergism appears to be multifactorial and involves interference with protein degradation as well as the interaction of myeloma cells with microenvironment.19 Vorinostat has been evaluated in the Vorinostat Clinical Trials in Hematologic and Solid Malignancies (VANTAGE) study program. The phase 2 VANTAGE 095 trial evaluated this agent in combination with bortezomib in bortezomib-refractory patients with MM (>2 prior therapies, N=143).20 Results suggest that the combination of vorinostat and bortezomib is active in patients whose disease is considered refractory to prior bortezomib and IMiDs, with an ORR of 17% reported in this trial. The median overall survival (OS) was 11.2 months with a 2-year OS rate of 32%. This combination therapy was generally well tolerated, with thrombocytopenia and gastrointestinal toxicities being the most common adverse events (AEs) reported.

The safety and efficacy of panobinostat in combination with carfilzomib is being evaluated in a phase 1/1b trial in patients with relapsed/refractory MM.21 The primary grade ≥3 toxicities were hematologic (thrombocytopenia, anemia, and neutropenia) and were manageable. Clinical benefit rate was determined to be 38%. Additionally, the triplet combination of panobinostat, bortezomib, and dexamethasone is currently being evaluated in a phase 3, randomized, placebo-controlled trial (PANORAMA-1).22 Romidepsin has also been investigated as triple therapy with bortezomib and dexamethasone in a phase 1/2 trial of patients with relapsed or refractory MM (patients having received ≥1 previous therapy). Encouraging activity was observed, with 72% of patients experiencing a minor response or better, and 4 of 6 patients (67%) who were refractory to bortezomib achieving disease stability

1. Liu FT, Agrawal SG, Movasaghi Z, et al. Dietary flavonoids inhibit the anticancer effects of the proteasome inhibitor bortezomib. Blood. 2008;112:3835-3846.

2. Golden EB, Lam PY, Kardosh A, et al. Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors. Blood. 2009;113:5927-5937.

3. Catley L, Anderson KC. Velcade and vitamin C: too much of a good thing? Clin Cancer Res. 2006;12:3-4.

4. Llobet D, Eritja N, Encinas M, et al. Antioxidants block proteasome inhibitor function in endometrial carcinoma cells. Anticancer Drugs. 2008;19:115-124.

5. Perrone G, Hideshima T, Ikeda H, et al. Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia. 2009;23:1679-1686.

6. Velcade (bortezomib) for Injection. Detailed View: Safety Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER). www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyRelatedDrugLabelingChanges/ucm123444.htm. Accessed August 6, 2013.

7. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132.

8. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142.

9. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.

10. Hirsh J. Risk of thrombosis with lenalidomide and its prevention with aspirin. Chest.

2007;131:275-277.

11. diCapua Siegel DS, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 (Ph 2) study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 985.

12. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70:1970-1980.

13. Kumar S, Bensinger WI, Reeder CB, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients with relapsed and/or refractory multiple myeloma: results from a phase 1 dose-escalation study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 816.

14. Richardson PG, Baz R, Wang L, et al. Investigational agent MLN9708, an oral proteasome inhibitor, in patients (Pts) with relapsed and/or refractory multiple myeloma (MM): results from the expansion cohorts of a phase 1 dose-escalation study. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 301.

15. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol. 2012;30:Abstract 8017.

16. Lawasut P, Chauhan D, Laubach J, Hayes C, et al. New proteasome inhibitors in myeloma.

Curr Hematol Malig Rep. 2012;7:258-266.

17. Schey S, Ramasamy K. Pomalidomide therapy for myeloma. Expert Opin Investig Drugs.

2011;20:691-700.

18. Jagannath S, Richardson PG, Hofmeister C, et al. Pomalidomide with or without low-dose dexamethasone in relapsed and refractory multiple myeloma: updated analysis. Haematologica.

2013;13(suppl 1):S143-S144. Poster P-210.

19. Hideshima T, Richardson PG, Anderson KC. Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther. 2011;10:2034-2042.

20. Siegel DS, Dimopoulos MA, Yoon SS, et al. VANTAGE 095: Final results from a global, single-arm, phase 2b trial of vorinostat in combination with bortezomib in salvage multiple myeloma patients. Haematologica. 2012;97(supp 1):119. Abstract 0294.

21. Shah JJ, Thomas SK, Weber DM, et al. Phase 1/1b study of the efficacy and safety of the combination of panobinostat + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4081.

22. Panobinostat or placebo with bortezomib and dexamethasone in patients with relapsed multiple myeloma (PANORAMA-1). NCT01023308. http://clinicaltrials.gov/ct2/show/NCT01023308.

Accessed August 6, 2013.

23. Harrison SJ, Quach H, Link E, et al. A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma. Blood. 2011; 118:6274-6283.

Nursing Considerations for Combination Therapy in Multiple Myeloma

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28. Kristinsson SY. Thrombosis in multiple myeloma. Hematology (ASH Education Program Book).

2010:437-444.

29. Boyle EM, Fouquet G, Manier S, et al. Immunomodulator drug-based therapy in myeloma and the occurrence of thrombosis. Expert Rev Hematol. 2012;5:617-626.

30. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423.

31. Nooka A, Gleason C, Casbourne D, Lonial S. Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib. Biologics Targets Ther. 2013;7:13-32.

32. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.

33. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934-1939.

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34. Lacy M, Gertz MA, Hayman SR, et al. Activity of pomalidomide plus dexamethasone (Pom/ dex) in dual lenalidomide/bortezomib refractory multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Proceedings). 2010;28(suppl):Abstract 8002.

35. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 866.

36. Richardson PG, Siegel DS, Vij R, et al. Randomized, open label phase 1/2 study of pomalidomide (POM) alone or in combination with low-dose dexamethasone (LoDex) in patients (pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): phase 2 results. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 634.

37. Pomalyst [package insert]. Summit, NJ: Celgene Corporation; February 2013.

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Immunotherapy

Immune-Related Endocrinopathies Associated With Ipilimumab Therapy Le Min, MD, PhD Brigham and Women’s Hospital, Boston, Massachusetts Nageatte Ibrahim, MD Dana-Farber Cancer Institute, Boston, Massachusetts

Key Points • Ipilimumab has improved the prognosis of patients with metastatic melanoma • Overall survival can now be talked about in terms of years rather than months • The majority of AEs associated with ipilimumab are considered to be immune-related and can include endocrine events • Patient education about the signs and symptoms of endocrinopathies (together with vigilance and prompt intervention on the part of the clinician) should help to ensure that endocrinopathies are appropriately managed

W

ith the recent advancements in the treatment of patients with metastatic melanoma, in particular with immunomodulating therapies, the development of unique immune-related side effects has posed novel management challenges. The first drug in this class to receive FDA approval for the treatment of unresectable stage III or IV melanoma is ipilimumab.1 Other antigen-independent immunomodulatory agents are currently in clinical development (eg, PD-1 inhibitors, PD-L1 inhibitors, and anti-CD137 antibodies). This review will focus primarily on the immunerelated endocrine side effects of ipilimumab.

Ipilimumab is a fully human monoclonal antibody that inhibits the binding of cytotoxic T-lymphocyte antigen-4 (CTLA-4) to its natural ligands on T cells, thereby augmenting antitumor T-cell activation and proliferation.2 Two phase 3 randomized trials demon-

strated a long-term overall survival (OS) benefit for ipilimumab.3,4 In the first study, 676 patients with previously treated metastatic melanoma were randomized to ipilimumab 3 mg/kg (administered IV every 3 weeks for 4 cycles) in combination with the experimental vaccine gp100, ipilimumab 3 mg/kg alone, or gp100 alone.3 Relative to gp100 alone, the risk of death was significantly reduced by ipilimumab plus gp100 (hazard ratio [HR] 0.68; P<.001) and by ipilimumab alone (HR 0.66; P=.003). In the second phase 3 trial, 502 patients with treatmentnaive advanced melanoma were randomized to treatment with ipilimumab 10 mg/kg (administered every 3 weeks for 4 cycles) plus dacarbazine or dacarbazine alone.4 The impact of ipilimumab on OS was confirmed in this study, as the median OS was significantly longer with ipilimumab plus dacarbazine compared with dacarbazine alone (11.2 vs 9.1 months; HR=0.72; P=.001).

Dr Min is an Associate Physician and Instructor in the Division of Endocrinology, Diabetes, and Hypertension at Brigham and Women’s Hospital, Harvard Medical School. His primary clinical and research interests include endocrinology, reproductive endocrinology, and tumor immunotherapy-related endocrinopathies.

Dr Ibrahim is a Medical Oncologist at Dana-Farber Cancer Institute and an Instructor of Medicine at Harvard Medical School.

Her primary clinical and research interests include melanoma, targeted therapeutics, and immunotherapies.

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Unlike conventional cytotoxic chemotherapy and targeted biotherapies, which act directly on tumor cells or oncogenic pathways, immunotherapies such as ipilimumab act to stimulate the body’s natural immune defense. As such, the response pattern seen with ipilimumab is different from that observed with conventional chemotherapy and targeted agents,5 where responses are durable for many months to years after therapy has stopped, and delayed responses are not uncommon. Furthermore, the adverse events (AEs) that have been reported with ipilimumab are consistent with an immune phenomenon as a consequence of CTLA-4 blockade.

These events, known as immune-related AEs (irAEs), may involve any organ system and are usually not severe if diligent monitoring and proactive management is in place. However, severe and even fatal irAEs have been reported in ipilimumab recipients, including enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathies.1 Endocrinopathies are less common than most other ipilimumab-related irAEs encountered in patients with metastatic melanoma.6 These events typically manifest during ipilimumab treatment, although some may develop even after discontinuation of therapy. They can be particularly severe if left untreated. It is important to recognize and address symptoms of endocrinopathies early to prevent the development of more serious events.

This review discusses ipilimumab-associated endocrinopathies and provides practical recommendations for timely recognition and treatment of these events.

CTLA-4 Inhibition With Ipilimumab and Associated Endocrinopathies During the adaptive immune response to tumor cells, T cells become activated when their receptors interact with tumor-associated antigens on specialized antigen-presenting cells (APCs) in a tightly regulated cascade of reactions requiring 2 signals.2,7-9 The first signal involves the T-cell receptor interacting with peptide­–major histocompatibility complex molecules on the membrane of APCs, upregulating T-cell expression of the inhibitory molecule, CTLA-4. The second

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Le Min, MD, PhD

Nageatte Ibrahim, MD

costimulatory signal involves B7 molecules on the APC surface binding with CD28 receptors on the T-cell surface. CTLA-4 competitively inhibits the binding of B7 to CD28, preventing the costimulatory signal and attenuating T-cell activation and proliferation.

Pharmacologic inhibition of CTLA-4 with ipilim­ umab prevents physiologic regulation of T-cell activation and proliferation, which may, in turn, elicit conditions that mimic those seen in autoimmune conditions, including endocrinopathies. Studies have

It is important to recognize and address symptoms of endocrinopathies early to prevent the development of more serious events. shown that the gene encoding CTLA-4 is an impor­ tant susceptibility locus for autoimmune-related endocrinopathies,10-13 and variant polymorphisms of the CTLA-4 gene have been linked to the presence of Graves’ ophthalmopathy.14 The exact mechanism of ipilimumab-associated endocrinopathies has not been elucidated. However, it is hypothesized to be due to endocrine organ infiltration by lymphocytes, which leads

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Table 1. Incidence of irAEs (Specifically Endocrine AEs) in Phase 2 and 3 Trials of Ipilimumab in Advanced Melanoma3,4,17-21 irAEs (%)

Endocrine AEs (%)

All Grades

Grade 3/4

All Grades

Grade 3/4

Ipilimumab 10 mg/kg q3w × 4 cycles, then maintenance q3m if eligible (n=71)

70.4

25.4

4.2

1.4

Ipilimumab 3 mg/kg q3w × 4 cycles, then maintenance q3m if eligible (n=71)

64.8

7.0

5.6

2.8

Ipilimumab 0.3 mg/kg q3w × 4 cycles, then maintenance q3m if eligible (n=72)

26.4

0

0

0

Study

Design

Treatment

Wolchok et al, 201017

Phase 2 randomized, double-blind study in previously treated patients

O’Day et al, 201018

Phase 2 single-arm, open-label study in previously treated patients

Ipilimumab 10 mg/kg q3w × 4 cycles, then maintenance q3m if eligible (n=155)

70.3

21.9

5.8

1.3

Weber et al, 200919

Phase 2 randomized, double-blind study in treatment-naive and previously treated patients

Ipilimumab 10 mg/kg q3w × 4 cycles + oral budesonide* or placebo, then ipilimumab maintenance if eligible (n=115)†

82.6

40.9

9.5

5.2

Hersh et al, 201120

Phase 2 randomized, open-label study in chemotherapy-naive patients

Ipilimumab 3 mg/kg q4w × 4 cycles + dacarbazine (n=35)

65.7

17.1

NR‡

NR‡

Ipilimumab 3 mg/kg q3w × 4 cycles alone (n=37)

53.8

7.7

NR‡

NR‡

NR§

NR§

3.9

1.1

Margolin et al, 201221

Phase 2 open-label study in 2 parallel cohorts of patients with advanced melanoma and brain metastases

Patients without glucocorticoids at baseline: ipilimumab 10 mg/kg q3w × 4 cycles, then maintenance q3m if eligible (n=51)

NR; similar between cohorts

Patients with glucocorticoids at baseline: ipilimumab 10 mg/kg q3w × 4 cycles, then maintenance q3m if eligible (n=21) Hodi et al, 20103

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Ipilimumab 3 mg/kg q3w × 4 cycles + gp100, then reinduction if eligible (n=380)

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irAEs (%) Study

Design

Hodi et al, 20103 (cont) Robert et al, 20114

Phase 3 randomized, double-blind study in treatment-naive patients

Endocrine AEs (%)

All Grades

Grade 3/4

All Grades

Grade 3/4

Ipilimumab 3 mg/kg q3w × 4 cycles alone, then reinduction if eligible (n=131)

61.1

14.5

7.6

3.8

gp100 alone (n=132)

31.8

3.0

1.5

0

Ipilimumab 10 mg/kg q3w × 4 cycles + dacarbazine, then dacarbazine alone q3w until week 22, then maintenance if eligible (n=251)

77.7

41.7

0

0

Dacarbazine alone q3w until week 22 (n=252)

38.2

6.0

0

0

Treatment

Monitoring of AEs occurred for at least 70 days after the last dose of the study drug had been administered. *Patients were randomized to treatment with oral budesonide to assess its impact on the incidence of grade ≥2 diarrhea. † AEs are reported for the study population as a whole, as oral budesonide did not influence ipilimumab safety profile. ‡ Only irAEs occurring in ≥5% of patients were tabulated in this study publication. § Only irAEs occurring in ≥15% of patients were tabulated in this study publication.

AE indicates adverse event; irAE, immune-related AE; NR, not reported; qxm, every x months; qxw, every x weeks.

to endocrine dysfunction. There is a predilection for anterior pituitary dysfunction in patients who develop ipilimumab-associated hypophysitis; however, it is not clear why the anterior pituitary is vulnerable to CTLA-4 blockage. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can also occur in the setting of ipilimumab-related hypophysitis.15 Isolated SIADH in patients receiving ipilimumab appears to be rare, but it may be underreported due to confounding etiologies such as progressive illness and concomitant medication use. It is also noteworthy that an association between hyponatremia and hypopituitarism with secondary adrenal insufficiency has been reported.16

Endocrinopathies Reported in the Clinical Trials With Ipilimumab in Advanced Melanoma A series of phase 2 and 3 trials have established the antitumor effects of ipilimumab, as well as an appropriate dose, and characterized the safety profile in patients with advanced melanoma.3,4,17-21 In most of these stud-

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ies, irAEs were monitored for up to 70 days following the last dose of treatment, a period equivalent to 5 ipilimumab half-lives. Endocrinopathies were one of the less common irAEs seen with ipilimumab, occurring in less than 10% of patients in any clinical trial (summarized in Table 1). It should be noted that specific treatment guidelines for endocrine AEs were outlined in the study protocols for the phase 2 and 3 clinical trials.

These guidelines included initiation of a short course of high-dose glucocorticoids to reverse inflammation, initiation of hormone replacement therapy, and modification of ipilimumab dosing, if necessary.

In a phase 2 dose-ranging study, patients with pretreated unresectable stage III or IV melanoma were randomized to induction treatment with ipilimumab 10 mg/kg, 3 mg/kg, or 0.3 mg/kg administered every 3 weeks for 4 cycles.17 Patients without progressive disease were able to continue treatment in a maintenance phase in which they received ipilimumab every 3 months. In this study, the frequency of irAEs (including endocrine AEs) was dose related. Grade 3 hypopituitarism in the

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Table 2. Endocrine AEs in a Phase 3 Trial Comparing Ipilimumab 3 mg/kg + gp100, Ipilimumab 3 mg/kg Alone, and gp100 Alone3 Ipilimumab + gp100 (n=380)

Ipilimumab Alone (n=131)

Total

Grade 3

Grade 4

Total

Grade 3

Grade 4

Total

Any endocrine

15 (3.9%)

4 (1.1%)

0

10 (7.6%)

3 (2.3%)

2 (1.5%)

2 (1.5%)

0

0

­­­­­ Hypothyroidism

6 (1.6%)

1 (0.3%)

0

2 (1.5%)

0

0

2 (1.5%)

0

0

Hypopituitarism

3 (0.8%)

2 (0.5%)

0

3 (2.3%)

1 (0.8%)

1 (0.8%)

0

0

0

Hypophysitis

2 (0.5%)

2 (0.5%)

0

2 (1.5%)

2 (1.5%)

0

0

0

0

Adrenal insufficiency

3 (0.8%)

2 (0.5%)

0

2 (1.5%)

0

0

0

0

0

Increase in serum thyrotropin level

2 (0.5%)

0

0

1 (0.8%)

0

0

0

0

0

Decrease in serum corticotropin level

0

0

0

2 (1.5%)

0

1 (0.8%)

0

0

0

Patients

gp100 Alone (n=132) Grade 3 Grade 4

From Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.

N Engl J Med. 2010;363:711-723. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

3-mg/kg group was noted among reasons for stopping treatment. Glucocorticoids and/or hormone replacement therapy was used to manage grade 3/4 endocrine events, which were all reported to have resolved or improved within 30 days of the last ipilimumab dose.

In a single-arm phase 2 study, patients with pretreated unresectable stage III or IV melanoma received induction treatment with ipilimumab 10 mg/ kg, administered every 3 weeks for 4 cycles, followed by maintenance ipilimumab every 3 months if eligible.18 Endocrine AEs were reported in 5.8% of patients at this dose and were symptomatically managed with glucocorticoids. One of the 2 patients with a grade 3/4 endocrine event did not have resolution of symptoms within the study period; therefore, median time to resolution of endocrine irAEs could not be estimated.

In an effort to determine whether prophylactic oral budesonide would reduce the rate of grade ≥2 diarrhea (another, more common irAE) in patients receiving ipilimumab, Weber and colleagues performed a random-

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ized, double-blind, phase 2 study comparing budesonide with placebo in treatment-naive and previously treated patients with advanced melanoma receiving ipilimumab 3 mg/kg, administered every 3 weeks for 4 cycles, followed by maintenance treatment if eligible.19 In this study, systemic steroids (principally oral, but also IV) were required to treat irAEs in 57% of patients in the prophylactic budesonide group and 44% in the placebo group. Interestingly, budesonide had no discernible impact on the incidence of any irAEs, including endocri­ nopathies, which occurred in 9% and 11% of patients in the budesonide and placebo arms, respectively. Of note, a low systemic bioavailability of budesonide due to an extensive first-pass liver metabolism may blunt its systemic effect.22 Hersh and colleagues evaluated ipilimumab 3 mg/ kg every 4 weeks for 4 cycles administered alone and in combination with dacarbazine in a phase 2, randomized, open-label study in chemotherapy-naive patients.20 Only irAEs reported in ≥5% of the study participants were

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Table 3. Frequency of Specific Endocrine AEs in a Pooled Analysis of Ipilimumab Phase 1 to 3 Clinical Trials (N=1498)6 Patients

Any Grade, n (%)

Grade 3/4, n (%)

Grade 5, n (%)

68 (4.5)

34 (2.3)

0 (0)

Hypopituitarism

40 (2.7)

31 (2.1)

0 (0)

Hypothyroidism

27 (1.8)

2 (0.1)

0 (0)

Adrenal insufficiency

11 (0.7)

5 (0.3)

0 (0)

Endocrine

Specific AEs shown in table are regardless of causality assessment. Subjects may have had more than 1 event. Unknown intensities are included in “Any Grade” column.

AE indicates adverse event; Grade 5, death.

Reprinted with permission. © 2011 American Society of Clinical Oncology. All rights reserved. Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol. 2011;29:(suppl). Abstract 8583. tabulated in this report; therefore, the incidence of endocrine AEs was not presented. However, it was noted that 1 patient receiving combination therapy developed serious or ongoing grade 2 adrenal insufficiency.

In the phase 3 registrational study comparing ipilim­ umab 3 mg/kg plus gp100, ipilimumab 3 mg/kg alone, and gp100 alone, endocrinopathies were categorized by subtypes, providing further insight into the types of endocrine dysfunction that might be expected with ipilim­umab (Table 2).3 Only 2 patients in the gp100 group experienced an endocrine AE, both of which were hypothyroidism. Of the 511 patients receiving ipilimumab, 25 (4.9%) reported an endocrinopathy, including hypothyroidism (1.6%), hypopituitarism (1.2%), hypophysitis (0.8%), adrenal insufficiency (1.0%), increase in serum thyrotropin level (0.6%), and decrease in serum corticotropin level (0.4%). Grade 3/4 endocrinopathies occurred in 9 ipilimumab-treated patients (1.8%), 6 of whom required hospitalization.1 All 9 patients had hypopituitarism, with some having additional endocrinopathies, including adrenal insufficiency, hypogonadism, and hypothyroidism. The median time to onset of moderate to severe endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of treatment.1 With the use of high-dose systemic glucocorticoids for the management of grade 3 or 4 irAEs (including endocrine irAEs), the median

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time to resolution of grades 2 to 4 irAEs was 6.3 weeks in the ipilimumab plus gp100 group, 4.9 weeks in the ipilimumab alone group, and 3.1 weeks in the gp100 alone group. Of the 21 patients with a grade 2 to 4 endocrinopathy, 17 required long-term hormone replace-

The median time to onset of moderate to severe endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of treatment. ment therapy, including adrenal hormones (n=10) and thyroid hormones (n=13).1 While the absolute number of ipilimumab recipients experiencing an endocrine AE is relatively small, the effects of such an event can be long-lasting; 8 of the 94 persons in this study who survived for at least 2 years after treatment initiation had residual effects of endocrine AEs that required ongoing hormone replacement therapy.

Interestingly, no endocrinopathies were reported in the phase 3 study comparing first-line ipilimumab 10 mg/kg plus dacarbazine with dacarbazine alone.4 A single case of hypophysitis was observed in a patient in the ipilimumab plus dacarbazine group, but since this event presented on day 364 after treatment initiation, which

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Table 4. Time to Onset and Resolution of irAEs23 Phase 3 MDX010-20 Any irAE Reported During Induction Phase

Pooled Phase 2 Data

Ipilimumab 3 mg/kg (N=131)

Ipilimumab 3 mg/kg (N=111)

Ipilimumab 10 mg/kg (N=325)

42

38

142

6.07 (3.43-7.29)

6.93 (4.86-7.57)

4.93 (4.00-5.57)

18

8

82

8.21 (7.00-10.90)

8.57 (5.86-11.70)

6.57 (6.14-7.86)

41

38

140

31 (75.6)

24 (63.2)

117 (83.6)

6.29 (4.29-8.43)

5.71 (2.14-15.10)

5.07 (3.86-7.14)

17

8

79

11 (64.7)

5 (62.5)

66 (83.5)

7.71 (3.00-21.70)

4.29 (0.57-NR)

4.57 (3.29-7.00)

Time to onset Grade 2-5, n Median weeks (95% CI) Grade 3-5, n Median weeks (95% CI) irAE time to resolution Grade 2-4, n Resolved, n (%) Median weeks (95% CI) Grade 3-4, n Resolved, n (%) Median weeks (95% CI)

Data are from phase 3 (MDX010-20) or from pooled phase 2 studies (CA184-004, CA184-007, CA184-008, CA184022; Table 1). Data presented were collected only during the initial induction phase of dosing. The proportion of patients that went on to receive additional therapy is small. irAE indicates immune-related adverse event; NR, not reached.

Reprinted with permission from Reinhard Dummer. was outside the protocol-specified reporting window of <70 days after the last dose of study medication, it was not categorized as an “on-study” event. It has been suggested that the unprecedented low endocrinopathy rate seen with ipilimumab in this study, despite its use at the higher dosage of 10 mg/kg, may be a collateral effect of coadministration of systemic glucocorticoids to manage hepatic AEs (occurring in approximately one-third of ipilimumab recipients); however, this hypothesis remains untested.

Ibrahim and colleagues have conducted a retrospective safety analysis of data from 14 ipilimumab clinical trials evaluating dosages ranging from 0.1 to 20 mg/kg (N=1498).6 Endocrine AEs were reported in 4.5% of the whole clinical trial population, with 2.3% of patients reporting grade 3/4 events (Table 3). More specifically, hypopituitarism, hypothyroidism, and adrenal

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insufficiency were reported in 2.7%, 1.8%, and 0.7% of ipilimumab recipients, respectively. A separate analysis of a smaller set of these trials reported time to onset and resolution of irAEs (Table 4).23 Endocrine events were not specifically analyzed; however, within 5 pivotal phase 2 and 3 trials, median time to irAE onset during induction was 5 to 9 weeks, depending on the dose of ipilimumab and the organ class affected; events managed according to treatment guidelines generally resolved within 4 to 8 weeks.

Several case reports on endocrine irAEs in patients with melanoma and other tumor types have been published (Table 5).15,24-30 In general, these events were reversible and manageable with glucocorticoids. Interestingly, adrenal insufficiency or corticotropin deficiency may persist despite recovery of other pituitary endocrine functions.24,25

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Table 5. Case Reports of Endocrine AEs Associated With Ipilimumab Therapy15,24-30 No. of Patients

Details of Endocrine AEs/Ipilimumab Therapy

Barnard et al, 201215

1

Pituitary enlargement, infundibulum enhancement, and enhancing, centrally necrotic foci in the anterior pituitary (ipi monotherapy)

Min et al, 201126

3

Thyroid autoimmunity 2 patients (ipi 10 mg/ Glucocorticoids for ophthalmopathy; kg + bevacizumab) and Graves’ ophthalmop- observation only for thyroid AEs athy 1 patient (ipi 10 mg/kg)

Carpenter et al, 200928

3

Ipilimumab-induced hypophysitis (all ipi 10 mg/kg)

Prednisone + levothyroxine; prednisone alone

Dillard et al, 201029

2

Hypopituitarism in prostate cancer patients (both ipi 10 mg/kg)

High-dose prednisone therapy, then tapered + levothyroxine; high-dose prednisone alone

Kaehler et al, 200930

1

Autoimmune hypophysitis

Steroid treatment

Blansfield et al, 200527

8

Autoimmune hypophysitis in melanoma (n=6) and renal cancer (n=2) patients (ipi 3-9 mg/kg)

High-dose steroids, followed by replacement hormones; replacement hormones alone

Min et al, 201224

7

Adrenal insufficiency. Symptoms included fatigue, malaise, lethargy, fever, or hypotension; headache in 5/7 patients. Onset of symptoms after ~9.4 weeks of therapy (all ipi 10 mg/kg; 4/7 patients ipi 10 mg/kg + bevaciz­ umab). Irreversible corticotropin deficiency.

Glucocorticoid + replacement hormones (levothyroxine and/or testosterone)

Yang et al, 200725

3

Autoimmune hypophysitis (2 patients) and adrenal insufficiency (1 patient) in renal cancer (ipi 3 mg/kg). Persistent adrenocortical insufficiency.

Replacement hydrocortisone + thyroxine (+ testosterone)

Study

Management Fluid restriction, hyperosmolar therapy, and steroids

AE indicates adverse event; ipi, ipilimumab.

Clinical Management of Endocrinopathies Associated With Ipilimumab The authors’ suggested approach for evaluating and managing ipilimumab-related endocrinopathies is presented in Figure 1. The authors recommend referral to an endocrinologist for workup and treatment in collaboration with the treating medical oncologist when an ipilimumab-associated endocrinopathy is suspected or develops. Patients treated with ipilimumab should be advised to immediately report symptoms that suggest

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the possible onset of an endocrinopathy, including fatigue, headache (generally described by patients as pressure behind the eyes), altered mental status, abdominal pain, unusual bowel habits, or hypotension.1 Other signs and symptoms of an endocrinopathy include lightheadedness, fevers, visual changes (including impaired eye movement, diplopia), palpitations, anxiety, decreased appetite, nausea, decreased libido (including impotence in men), polyuria, and cold/heat intolerance. Because these symptoms are nonspecific and can be attributed to other causes, such as underlying disease

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Figure 1. Monitoring for and Managing Ipilimumab-Related Endocrinopathy TSH, free T4 and AM cortisol prior to each dose of ipilimumab

History and physical (symptoms and signs suggestive endocrinopathies)

Morning paired ACTH and cortisol (Omit narcotics from 12 MN if possible) Gonadotropins and testosterone (in men) Secondary adrenal insufficiency

Primary adrenal insufficiency

Secondary hypothyroidism

Low cortisol, low ACTH (exclude medications and critical illness)

High/normal ACTH or signs suggestive of primary adrenal insufficiency

Low TSH and low free T4 (exclude nonthyroidal illness)

Start glucocorticoids replacement Pituitary MRI Enlarged pituitary: formal visual field test

Cosyntropin stimulation test Start glucocorticoids and mineralcorticoids replacement

Low TSH and high free T4 Thyroid uptake test

Start levothyroxine replacement Pituitary MRI Enlarged pituitary: formal visual field test

Low gonadotropins and low testosterone in men (exclude critical illness and confirmed by repeat morning total testosterone and SHBG)

High uptake: Graves disease

Low uptake: thyroiditis

Start testosterone replacement if no contraindication

Start Methimazole

Beta-blocker for symptomatic thyrotoxicosis

Enlarged pituitary: formal visual field test

Pituitary MRI

Hold ipilimumab until symptoms resolve and on stable hormone replacement High dose glucocorticoids for life threatening endocrinopathies

ACTH indicates adrenocorticotropic hormone; SHBG, sex hormone-binding globulin; T4, thyroxine; TSH, thyroidstimulating hormone.

or brain metastases, they may go unattended or inappropriately recognized and managed, thereby allowing the development of a more serious illness.

Thyroid function tests, morning cortisol, and clinical chemistries should be monitored at the start of treatment, before each dose, and as clinically indicated based on signs and symptoms, particularly in the first 3 months of treatment with ipilimumab.26 Abnormalities in these tests may indicate development of an ipilimumab-associated endocrinopathy. Unless an alternative etiology is identified, signs and symptoms of endocri­ nopathies should be considered an irAE. In patients with clinical or biochemical thyrotoxicosis, a thyroid uptake test will help to distinguish between thyroiditis and Graves’ disease. If patients have symptoms suggestive of adrenal insufficiency, paired morning cortisol and adrenocorticotropic hormone (ACTH) should be measured. Certain medications, such as opiates and glucocorticoids, can interfere with the interpretation of these studies and therefore should be held off for at least 8 to 10 hours before cortisol and ACTH tests. High-

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dose glucocorticoids such as dexamethasone suppress the hypothalamic-pituitary-adrenal axis (Figure 2). If primary adrenal insufficiency is suspected, a cosyntropin stimulation test should be performed to confirm the diagnosis. If the patient is on glucocorticoids (except dexamethasone), measuring aldosterone at basal level and 30 minutes after cosyntropin stimulation will help to identify primary adrenal insufficiency. A greater than 5 µg/100 mL increase in aldosterone level usually rules out primary adrenal insufficiency.31 When the initial workup shows central hypothyroidism or secondary adrenal insufficiency, other anterior pituitary hormone levels should also be measured to determine the underlying etiology. In patients with hypophysitis, further tests may reveal low blood levels of luteinizing hormone, follicle-stimulating hormone, insulin-like growth factor 1, and prolaction. Effects of critical illness on the hypothalamic-pituitary axis should be taken into consideration before making the diagnosis of a hypophysitis-related endocrinopathy. Symptoms and signs suggestive of diabetes insipidus or diabetes melli-

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tus, such as polydipsia and polyuria, should be addressed during each clinic visit. During ipilimumab therapy, blood glucose levels should be monitored periodically.

Ipilimumab treatment should be withheld in patients with symptoms suggestive of an endocrine event until complete resolution or the patient is stable on hormone replacement therapy. There is no consensus on glucocorticoid dosing in patients with ipilimumab-related endocrinopathies. We recommend individualized management.

Usually, systemic glucocorticoids (prednisone 1-2 mg/kg/day or equivalent) should be initiated in patients with a symptomatic endocrinopathy, together with appropriate hormone replacement therapy.1 We recommend that all patients receiving ipilimumab also receive glucocorticoid treatment if they have clinical symptoms or biochemical evidence of adrenal insufficiency, starting with a physiologic dose of hydrocortisone or prednisone unless symptoms persist.

Some studies have suggested that systemic glucocorticoids do not appear to counteract ipilimumab activity,19,32 although this has been questioned in other studies.21 Until the impact of glucocorticoids on the antitumor effects of immunotherapy has been evaluated in robust randomized trials, we advise avoiding high-dose glucocorticoids, if possible. We have successfully managed many patients with ipilimumab-related hypophysitis by utilizing a physiologic dose of glucocorticoids (â&#x2030;¤5 mg prednisone or equivalent). However, if there are any signs of adrenal crisis (ie, severe dehydration, hypotension, and shock), IV glucosteroids with mineralocorticoid activity, such as hydrocortisone, should be initiated immediately. Once symptoms and/or abnormal lab values are controlled and the patient has clinically improved, a slow steroid taper (over at least 1 month) should be initiated based on clinical judgment.

The abrupt discontinuation of glucocorticoids should be avoided due to possible prolonged adrenal suppression.

Rarely, a patient may persistently have an enlarged pituitary on MRI and continue to be symptomatic (eg, headache, visual disturbances). A short course of highdose glucocorticoids, such as dexamethasone 4 mg every

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Figure 2. Hypothalamic-Pituitary-Adrenal Axis Hypothalamus

Cortisol

T3, T4 TRH CRH Pituitary

ACTH

TSH GH

PRL

FSH, LH

Adrenals

Thyroid Mammary Tissue

Steroid Hormones

Muscles and Bones

Gonads

ACTH indicates adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; PRL, prolactin; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.

6 hours, should be considered to treat the presumed underlying pituitary inflammation. Lifelong glucocorticoid therapy and/or hormone replacement therapy may be necessary. Ipilimumab should be permanently discontinued in cases where the glucocorticoid dose cannot be reduced to 7.5 mg prednisone or equivalent

There is no consensus on glucocorticoid dosing in patients with ipilimumab-related endocrinopathies. We recommend individualized management. per day, and in cases where the patient cannot complete the full treatment course within 16 weeks from administration of the first dose of ipilimumab.

It is important to note that growth hormone should not be used as hormone replacement therapy, as this agent is contraindicated in patients with an active malignancy. Patients with Gravesâ&#x20AC;&#x2122; disease should receive antithyroid treatment, such as methimazole and/or radioiodine ablation. Antithyroid treatment

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should not be administered to patients with thyroiditis; rather, symptomatic patients should be treated with a beta-blocker such as propranolol or atenolol, or with

glucocorticoids in patients with cardiac diseases that increase the risks for arrhythmia.

In male patients with androgen deficiency, testos-

Case Study: Management of Ipilimumab-Associated Endocrinopathy We describe a case to illustrate how ipilimumab-related endocrinopathies are diagnosed and managed. A 68-yearold male with stage IV melanoma started on ipilimumab 3 mg/kg IV every 3 weeks. He developed a new-onset headache – which he described as a frontal headache with pressure behind his eyes – after 3 doses of ipilimumab, 9 weeks following initiation of ipilimumab therapy. He reported fatigue and low libido that were gradually progressive along with the headache over 2 weeks. Biochemical testing done in the morning revealed undetectable corticotropin and low cortisol, suggestive of secondary adrenal insufficiency; inappropriate normal gonadotropins and undetectable testosterone, suggestive of hypogonadotropic hypogonadism; and low thyrotropin (TSH) and slightly low thyroxine concentrations, suggestive of central hypothyroidism or nonthyroidal illness syndrome. Prior to dose 1 of ipilimumab therapy, he had normal thyroid function tests. He was treated with physiologic doses of hydrocortisone and testosterone with resolution of his symptoms.

An MRI of the brain revealed dynamic changes in his pituitary gland: normal size prior to ipilimumab, prominence of the pituitary gland 1 month after initiation of ipilim-

A

umab, and normal size 5 months after ipilimumab therapy (Figure). Prior to testosterone replacement, his blood levels of PSA and hematocrit were 0.58 ng/mL and 43.8%, respectively. Ipilimumab therapy, dose 4, was resumed 1 week after he was started on hormone replacement, as he was asymptomatic. He did not receive levothyroxine replacement but had periodic monitoring of his thyroid function; his blood levels of TSH and thyroxine normalized subsequently. The patient was able to safely complete the full course of induction with ipilimumab in 16 weeks, after which subsequent scans showed stable disease. Of note, his symptoms of headaches, malaise, and decreased libido preceded the decrease in hormone levels, so vigilant monitoring is vital in making the diagnosis and management. There are cases in which the pituitary enlargement is seen on MRI prior to the drop in hormone levels; these patients should be managed symptomatically with the institution of glucocorticoids based on the degree of their symptoms (eg, headaches, visual disturbances). High-dose IV glucocorticoids (eg, methylprednisolone) may be necessary, especially if they do not respond to physiologic oral steroid replacement.

B

C

Figure. MRI of the Brain: (A) Patient Prior to Treatment; (B) 1 Month Following Treatment With Ipilimumab; and (C) 5 Months Following Treatment With Ipilimumab

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terone replacement may be indicated. Prostate-specific antigen (PSA) and hematocrit should be evaluated prior to starting treatment because testosterone replacement therapy is contraindicated in several patient groups, including those with prostate cancer, PSA >4 ng/mL (>3 ng/mL in high-risk groups such as African Americans and men with a first-degree relative with prostate cancer), an unevaluated prostate nodule or induration, severe lower urinary tract symptoms associated with benign prostatic hypertrophy, and hematocrit >50%. Other contraindications include breast cancer, uncontrolled or poorly controlled congestive heart failure, and untreated sleep apnea.

Testosterone levels, PSA, and hematocrit should be evaluated 3 to 6 months after initiation of testosterone replacement therapy and then periodically according to guidelines.33 Patients with adrenal insufficiency and their families should be aware of “sick day rules” and emergency management of an adrenal crisis, including how to self-inject hydrocortisone intramuscularly. Patients with adrenal insufficiency or hypophysitis should be encouraged to wear a MedicAlert bracelet or necklace. Depending on the severity, hyperglycemia can be managed by diet control or insulin basal plus a bolus regimen.

Conclusion Ipilimumab has improved the prognosis of patients with metastatic melanoma such that OS can now be talked about in terms of years rather than months. The majority of AEs associated with ipilimumab are considered to be immune-related and can include endocrine events. While these events are relatively uncommon and have nonspecific symptoms, they can be life threatening if left untreated. Patient education about the signs and symptoms of endocrinopathies, together with vigilance and prompt intervention on the part of the clinician, should help to ensure that endocrinopathies are appropriately managed and resolve in a timely manner. Successful management of endocrinopathies will also enable the safe administration of subsequent ipilim­umab doses.

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Acknowledgments The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical expertise. The authors also wish to acknowledge StemScientific, funded by BristolMyers Squibb, for providing writing and editorial support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript. u

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19. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591-5598.

20. Hersh EM, O’Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Invest New Drugs. 2011;29:489-498.

21. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol.

2012;13:459-465.

22. Ryrfeldt A, Andersson P, Edsbäcker S, et al. Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid. Eur J Respir Dis Suppl. 1982;122:86-95.

23. Dummer R, Maio M, Hamid O, et al. Time to onset and resolution of immune-related adverse events associated with ipilimumab therapy in patients with advanced melanoma. Paper presented at: Perspectives in Melanoma XIV; September 17-18, 2010; Amsterdam, the Netherlands.

Abstract P-0004.

24. Min L, Vaidya A, Becker C. Association of ipilimumab therapy for advanced melanoma with secondary adrenal insufficiency: a case series.

Endocr Pract. 2012;18:351-355.

25. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825-830.

26. Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to melanoma biologic therapy. Eur J Endocrinol. 2011;164:303-307.

27. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593-598.

28. Carpenter KJ, Murtagh RD, Lilienfeld H, et al. Ipilimumab-induced hypophysitis: MR imaging findings. AJNR Am J Neuroradiol.

2009;30:1751-1753.

29. Dillard T, Yedinak CG, Alumkal J, et al. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary. 2010;13:29-38.

30. Kaehler KC, Egberts F, Lorigan P, et al. Anti-CTLA-4 therapyrelated autoimmune hypophysitis in a melanoma patient. Melanoma Res. 2009;19:333-334.

31. Dluhy RG, Himathongkam T, Greenfield M. Rapid ACTH test with plasma aldosterone levels. Improved diagnostic discrimination. Ann Intern Med. 1974;80:693-696.

32. Grob JJ, Hamid O, Wolchok J, et al. Antitumor responses to ipilimumab in advanced melanoma are not affected by systemic corticosteroids used to manage immune-related adverse events (irAEs). Paper presented at: Joint ECCO 15-34th ESMO Multidisciplinary Congress; September 20-24, 2009; Berlin, Germany. Abstract P-9312.

33. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559.

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ASCO President Focuses on Bridges to Conquer Cancer Wayne Kuznar

“Building Bridges to Conquer Cancer” was the theme of the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO), as well as the address of ASCO president Sandra M. Swain, MD. Her address focused on 3 pillars of the theme: 1) ensuring global health equity, 2) the need to strengthen future generations of leaders and practitioners, and 3) the vision for a rapid learning system in oncology.

These 3 issues “belong squarely on our personal and professional radar screens,” she said.

Global Health Equity Gaps in connecting proven treatments and preventive measures with underserved populations are linked to higher mortality from cancer and more suffering due to later stages of presentation.

These gaps occur in different parts of the United States, and not just in low- and middle-income countries, said Swain. Forty-eight million uninsured Americans – and those joining the Medicaid rolls – are all part of this picture. One area of concern is the wide variability in Medicaid programs.

“On the plus side, a recent study showed that in states where Medicaid programs have been expanded to cover more individuals, there has been a reduction in overall mortality,” she said. “While this is an encouraging sign for the general population, cancer-specific outcomes for patients covered by Medicaid have been associated with no better outcomes than for those who are uninsured.”

A key predictor of whether an adult will survive cancer is income. This outcome gap is largely a result of differences in access to care. One innovative effort to bridge equity gaps is a screening program for colon cancer that is available to every citizen in Delaware.

The program’s success is exemplified by screening rates in African Americans that rose from 48% to 74%. The number of African Americans presenting with regional and distant colorectal cancer was reduced by 39%. The

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decline in mortality rates for African Americans was 42%, bringing it closer to that of whites.

“Not only did the program help patients avoid the pain and suffering associated with aggressive treatment of late-stage illness, it saved millions of dollars in treatment costs,” said Swain.

Although advances have been made in vaccines and the screening of large populations for breast and cervical cancers, many of these methods are not available globally. And even if the cancer is diagnosed, there are wide gaps in the availability of affordable treatments.

In response to the global cancer crisis, ASCO has started a program called ASCO International, which aims to increase support for existing programs and invest in new programs targeted at global cancer control.

One important strategy will be to use digital resources (ie, virtual meetings and mentoring) “to knit the world closer together.”

Supporting the Next Generation of Leaders and Practitioners Supporting the next generation of clinical cancer researchers is a priority, said Swain. Although 98% of past winners of the Young Investigator Award and Career Development Awards programs are still involved in cancer research, donations to support the programs are declining, an unwelcome occurrence at a time when federal research dollars are dwindling.

ASCO is continuing its successful and popular Leadership Development Program in an effort to develop the next generation of leaders, but potential shortfalls in practicing oncologists is a concern. “Will we be able to meet the projected increase in cancer cases? To better understand and monitor these trends, ASCO has established a Workforce Information System,” she said.

At present, the number of oncologists 64 years and older is growing rapidly and outnumbers those younger than 40 years. Further, only 3% of oncology fellows are African American, and 8% are Hispanic. In order to

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address the disparities in access to cancer care, a diverse professional workforce is necessary.

Accelerated Learning for a Data-Driven Era “To create a world free from the fear of cancer, we must accelerate our knowledge about the disease, its biology, and its treatment,” said Swain.

To this end, ASCO has launched CancerLinQ, a rapid learning system that aims to use real-time information from every patient experience both to guide day-to-day care and inform clinical guidelines on a real-time basis. “A rapid learning system will transform information that is now locked away in filing cabinets, patient records, lab reports, journals, disconnected electronic records, and inside our overloaded brains into real insight,” she said. “We need to be able to use

the 97% of patient information that is currently lost.”

A physician can query a CancerLinQ database to discover current practices in the management of a particular cancer and the outcomes obtained. “By stitching together many stories, we can gain understanding of what worked and didn’t for thousands of patients – not just the 3% who may have been in a clinical trial,” she said.

Ultimately, understanding patient experiences can guide research questions, bridge gaps in knowledge, and provide critical information for situations in which randomized controlled trials are not feasible or possible.

CancerLinQ has been advanced with the development of a prototype that contains de-identified data on more than 130,000 patients with breast cancer “By using a combination of open source and other software, we have shown it’s possible to obtain and aggregate information from different electronic health records,” she said. u

Multiple Myeloma: Novel Agents Emerge in Initial Therapy, Refractory Setting Wayne Kuznar

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dvances in the understanding of the biology of multiple myeloma (MM) and the identification of new drugs have resulted in improved management of MM, including patients who are refractory to proteasome inhibitors and immunomodulatory agents.

An update on initial therapy was offered by Donna E. Reece, MD, director, Program for Multiple Myeloma and Related Diseases, Princess Margaret Cancer Center, Toronto, Ontario, Canada.

Myeloma consists of at least 7 subtypes based on cytogenetics and molecular features. The highest-risk subtypes by fluorescence in situ hybridization are t(4;14), t(14;16), del(17p), and chromosome 1 abnormalities; all are recognized as adverse prognostic factors.

An evolving US treatment algorithm recommends treating younger patients, particularly those with standard-risk disease, with regimens based on novel agents

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such as thalidomide, bortezomib, and lenalidomide before autologous stem cell transplantation (ASCT).

After ASCT, bortezomib-based therapies have increased the median progression-free survival (PFS) to 3 years compared with 2 years achieved with older regimens such as VAD (vincristine, doxorubicin, and dexamethasone) or thalidomide plus dexamethasone induction, Reece said. Bortezomib-containing regimens as induction also yield better response rates and overall survival (OS) compared with these older regimens. The inclusion of bortezomib, particularly in a 3-drug regimen, seems important for high-risk disease, as indicated by the recent integrated analysis of the 4 phase 3 studies of bortezomib induction.

Thalidomide as a single agent or in conjunction with corticosteroids as post-ASCT maintenance improved both PFS and OS in a meta-analysis of 7 phase 3 clini-

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cal trials. Lenalidomide maintenance has been assessed in 2 phase 3 trials, demonstrating significant prolongation of PFS and time to progression.

“Advantages of consolidation [moderately intensive combination therapy given for several cycles after recovery from ASCT] compared with long-term maintenance therapy include a finite period of treatment and, potentially, a lower and more predictable cost,” said Reece. In the future, consolidation with a 3-drug combination would ideally be integrated into therapy, particularly in the high-risk setting.

In elderly patients, the addition of a novel agent (ie, thalidomide, bortezomib, or lenalidomide) to melphalan and prednisone results in a better antimyeloma effect, although the incidence of grade 3/4 toxicity is relatively high. Lenalidomide plus weekly dexamethasone is also a promising regimen in elderly patients.

More frequent use of proteasome inhibitors and immunomodulatory agents as part of initial therapy and in the maintenance setting has contributed to drug resistance, which portends a poor prognosis. New therapeutic strategies are needed in this challenging population, said Robert Z. Orlowski, MD, PhD, professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX.

KSP Inhibitor A novel strategy targets kinesin-spindle protein (KSP), said Orlowski. ARRY-520 is a potent, highly selective KSP inhibitor that was studied in a phase 2 trial as both a single agent (cohort 1) and in combination with low-dose dexamethasone (cohort 2). After a median treatment time of 3.9 months, the ORR was 22%, and the median duration of response was 5.4 months.

In cohort 1, 53% had disease refractory to bortezomib, and 75% had disease refractory to lenalidomide. Of 32 patients in cohort 1 with assessable response, ORR was 16% (5 partial responses).

Carfilzomib, Pomalidomide Potent analogues of existing MM drugs, such as carfilzomib and pomalidomide, have demonstrated clinical efficacy in the double-refractory setting, resulting in the recent approval of both drugs. Carfilzomib in patients with relapsed or refractory MM was associated with an overall response rate (ORR) of 15.4%, with a median duration of response of 7.8 months. Median OS was 15.6 months in the overall population and 11.9 months in the double-refractory subgroup.

Pomalidomide has been shown to be active against

Daratumumab Daratumumab is an investigational human monoclonal antibody that has received breakthrough therapy designation from the FDA for the treatment of patients with MM who have received at least 3 prior lines of therapy or who are double refractory to a proteasome inhibitor and an immunomodulatory agent. A phase 1/2 dose escalation study in 32 patients with relapsed MM showed at least a minimal response in 8 of the 12 patients who received 4 mg/kg or higher of daratumumab, with no major safety issues. u

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double-refractory MM in several phase 2 and phase 3 trials. The ORR was 31%, PFS was 3.8 months, and OS was 13.8 months in patients with relapsed/refractory MM who were randomized to pomalidomide with weekly dexamethasone.

In a phase 3 trial, patients were randomly assigned to either pomalidomide and low-dose dexamethasone or single-agent high-dose dexamethasone. In patients with double-refractory disease, median PFS in the pom‑­ alidomide arm was 3.2 months versus 1.7 months in the high-dose dexamethasone arm (P<.001); median OS was not reached in the pomalidomide arm, whereas median OS in the high-dose dexamethasone arm was 7.4 months (P<.001), said Orlowski.

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PM O

Interview With the Innovators A PMO Exclusive Series 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 personalizing oncology care.

To view Interview With the Innovators, or to nominate an interviewee, visit us at

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PMO Interviewees include:

Michael Pellini, MD Foundation Medicine Inno52013

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Kimberly Popovits Genomic Health

Henry T. Lynch, MD Creighton University School of Medicine

2013 ASCO Annual Meeting

Ten Years of Tamoxifen Is Superior to 5 Years in ER+ Breast Cancer Wayne Kuznar

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en years of adjuvant tamoxifen is superior to 5 years in reducing the rates of late recurrence and death in women with estrogen receptor (ER)positive breast cancer, reported Richard G. Gray, MSc. Previously, 5 years of tamoxifen have been shown to reduce breast cancer mortality by about one-third over 15 years. Gray presented data from a study known as aTTom (Adjuvant Tamoxifen: To Offer More?), which demonstrated an additional 25% reduction in cancer recurrence and death rates from year 10 onward in women treated for 10 years compared with 5 years of tamoxifen.

The aTTom results complement and confirm those from a recently published study called ATLAS (Adjuvant Tamoxifen: Longer Against Shorter; Lancet.

2013;381:805-816).

In aTTom, 6953 women in the United Kingdom who had been taking tamoxifen for 5 years were randomized to continuing treatment for an additional 5 years or stopping treatment. About 75% of the women assigned to continue tamoxifen had continued taking it for the 5 extra years.

Ten years of tamoxifen reduced breast cancer recurrence by 15% compared with 5 years (P=.003). The rate of breast cancer deaths was reduced by 12% with 10 years relative to 5 years (P=.06). “Treatment allocation had little effect on either recurrence rates or death rates from 5 to 9 years after diagnosis, but the benefit of longer treatment became evident in the second decade after diagnosis,” said Gray, professor of medical statistics at the University of Oxford, United Kingdom. The relative reduction in the risk of death with assignment to 10 years of tamoxifen increased to 21% in years 10 to 14 after diagnosis, and to 25% in year 15 of follow-up and later.

There were no significant differences in the rates of death without recurrence or all-cause mortality between

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the 2 groups, although a significant difference in overall survival in favor of 10 years of tamoxifen emerged from year 10 onward (P=.016).

Extending the use of tamoxifen approximately doubled the risk of endometrial cancer (from 1.3% to 2.9%) and endometrial cancer death (from 0.6% to 1.1%), but the net clinical benefit favored 10 years of treatment, he said.

Compared with not taking tamoxifen, 10 years of tamoxifen reduces the breast cancer death rate by onethird in the first 10 years after diagnosis and by half subsequently, said Gray. The benefit of tamoxifen in the aTTom study may be even greater than reported because 60% of the enrolled patients had an unknown ER status. An estimated 15% of patients likely had ERnegative disease and did not benefit from tamoxifen.

The findings from aTTom complement and confirm those from ATLAS. The combined data of aTTom and ATLAS, with more than 17,000 patients, show a significant 15% reduction in breast cancer mortality overall (P=.001) and an additional 25% reduction in breast cancer mortality 10 years and beyond with 10 years of tamoxifen compared with 5 years of treatment (P=.00004).

Together, the results of the aTTom and ATLAS trials constitute “proof beyond reasonable doubt” that continuing tamoxifen beyond 5 years reduces the risk of late recurrence and reduces breast cancer mortality, said Gray.

Late relapses remain a concern in ER-positive breast cancer, even with the introduction of effective early therapies, said Ann H. Partridge, MD, MPH, medical oncologist, Dana-Farber Cancer Institute, Boston, MA, and extended tamoxifen therapy appears to reduce the risk of late relapses. In aTTom and ATLAS, extending tamoxifen primarily reduced the risk of recurrences starting after year 7. u

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The Last Word

Immunotherapy in Cancer Care: Personalized or Population-Based Medicine…and the Janusian Factor

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s immunotherapy a type of personalized medicine cer has raised hopes for these patients, but when I asked a (PM) or just useful population-based medicine? leading expert in prostate cancer, he stated categorically Look in different directions and you’ll get differthat it is not PM: “It is given to everybody that fits a ent answers, but whatever we do, let’s avoid oversimclinical profile, and one day we might choose it on the plification. For when we get down to basis of a personal trait or tumor trait, specifics, the accurate answer is, “It debut not yet.” pends.” When in doubt, it is often useThis brings us back to the realities ful to consult cutting-edge researchers of PM in oncology (and elsewhere): and, every now and then, the Classical it is the preferred quality of a meditradition. I offer the findings of a study cation or procedure, but meanwhile published in Nature, “Cancer Immuwe operate in a “split system” of popnotherapy Comes of Age,” the evaluaulation-based and PM. The former is tion of a leading prostate cancer expert a game of chance, the latter an enconcerning sipuleucel-T (Provenge), riched patient base where we know (to and finally, the perspective of Janus, a certain degree) whether a particular that obscure Roman god who insisted patient is capable or incapable of reRobert E. Henry on looking both ways. In the end, we sponding to a drug or procedure. And wind up with answers to the practical the latter is the criterion for PM. clinical management of cancer and some much-needed We might have expected this answer in the case of clarification of what is meant by PM. sipuleucel-T (though we shouldn’t expect anything eiFirst we turn to the fact that immunotherapy is now ther way!). The common thinking in vaccine therapy is capturing the imagination of the oncology world. The mass administration in the hope of helping some of the study in Nature by Mellman, Coukos, and Dranoff exults recipients, without having any idea which are the best in “…the ability of the anti-CTLA4 antibody, ipilim­ candidates and which should be ruled out a priori. The umab, to achieve a significant increase in survival for topic helps reinforce our awareness of what PM is and patients with metastatic melanoma, for which convenhow today’s practicing oncologists are forced to structional therapies have failed. In the context of advances ture treatment strategies: a mixed bag of personalized in the understanding of how tolerance, immunity and and population-based medicine. immunosuppression regulate antitumour immune reWhile it may seem that because PM is a diffuse consponses together with the advent of targeted therapies, stellation of screening tactics ranging from hard science these successes suggest that active immunotherapy repto soft personal patient considerations, all new therapies resents a path to obtain a durable and long-lasting refall within its boundaries. But the truth of PM is that its sponse in cancer patients.” broad scope does not make its boundaries sloppy. The But wait…the authors may be ecstatic at the use of core PM criterion is fiercely simple, in fact, as described ipilimumab within the context of PM, but they do not dein stark simplicity by the aforementioned prostate cancer scribe it as PM itself. That makes it perhaps a semi-PM expert. It is treatment chosen “on the basis of a personal regimen component, at least for now. And the recent trait or tumor trait.” This principle may be simple, but FDA approval of sipuleucel-T for advanced prostate canthe determinants are anything but. The enriched patient

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base that takes the guesswork out of drug or procedure choice for an individual patient is dizzyingly deep; it simply has to meet this core condition.

So the vaccine administered solely on the basis of the disease’s stage of progression, the patient’s raw symptoms, or demographic niches, remains outside the pale of PM. Such a drug is being administered on population-based criteria: average response rates to the drug regimen for anyone with advanced prostate cancer. But the moment a biomarker or other qualifying predictor (eg, nomogram – quite popular in prostate cancer, which has a paucity of biomarkers) is proven to predict the likelihood of response/nonresponse, the regimen crosses over into PM. It is that simple.

It is treatment chosen “on the basis of a personal trait or tumor trait.” This principle may be simple, but the determinants are anything but.

So much for the attempt to oversimplify the dual issue of immunotherapy and PM, to equate all progress with PM, and demoting population-based medicine – immunotherapy or otherwise – as passé or antiquated.

The advent of PM has been, and will remain, an iterative one, putting a Janusian face on cancer treatments.

Yes, Janusian – I haven’t forgotten my promise to bring in the Classics. Janus was the ancient Roman god of beginnings and endings, doorways and transitions. This two-faced god looked to the future and the past, whence we derive the month January. Cancer treatment is a

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pragmatic business, looking desperately in multiple directions at once for any remedy – PM or non-PM – that will conquer the cancer destroying its human host.

The sage oncologist is cognizant of the superiority of PM-advised regimens over conventional ones, just as today’s savvy shopper seeks organic produce over conventionally raised food. But where organic produce is unavailable, the shopper does not cease to eat. In both scenarios, medical and shopping, the real-world resources available require the perfect and imperfect to be used side by side to sustain life. In this pragmatically run race against time and cell replication run amuck, the clinical oncologist welcomes every assist that increases the chance to outrun the killer disease.

Thus, the answer to the question of whether immunotherapy is part of PM in cancer is not to be confused with whether immunotherapy is good or bad medicine.

Immunotherapy is not inherently PM or non-PM; it can achieve PM status as readily as any other drug, providing it meets the aforementioned criterion of being targeted treatment. Where it remains outside the pale of PM, this should only spur researchers to find that qualifying “personal trait or tumor trait” needed to enhance its usefulness, its predictability.

When the ancient Romans devised the Janus myth, they were extolling the need to look ahead and behind for answers to vexing problems. That dynamic is alive and well in cancer care.

Robert E. Henry

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

vention and relief of suffering by means of early identiam enthusiastic about this 6-part series titled Confication and impeccable assessment and treatment of quering the Cancer Care Continuum. Each edition of pain and other problems, physical, psychosocial, and CCCC will address an important topic in oncology RIES spiritual.” (http://www.who.int/cancer/ management and offer expert E 2013 SE THstakeIN UE ISS palliative/en/).

IRD commentaries. Topics will THholder For too long, however, the image of include: palliative care, pain manageNU AN - AL ND CO ™ palliative care has been tied exclusively ment, hospice SE care, comprehensive to end-of-life care and focused solely on treatment planning, survivorship care, pain control. and the role of biosimilars in supportLillie D. Sho ckney, RN, BS, MAS The articles that follow provide a ive care. In this issue, we address paln part 2 of our clear understanding of the intent of liative care.

Conquering series, the 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 cancer provideddie for wh theile dying. providers as well as patients) uncom- we still me it effe l agecare designed as tica nts, as have a ctively, fear 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. Family members, they will sucD.alf Shockney, of our patiRN, their grea nes I wasLillie scare too, com theirforlov ent ciated with quality-of-life alled to speak with members of our palliative recently s.

BS,wat MAS one in grea test fear is having ute chi to wit t pai care team at Johns Hopkins and learned ern s of an old, black-a ng a few min- cancer patients and survivors, no mat- ease the sufferin n without a way nd-white movie. A to wes g. cow ter what their clinical outcome. that the word “palliative” comes from the word “palliare,” tfear Fam boy had by a gunslin these will ily memb been sho be the fina ers ger, and as Your wit t nes cancer patients may not tell you about the side which means to disguise or cloak. Centuries ago,mp this word tor atte l ima s before the ted to rem the town docir loved oneges they Ma ove ny effects of treatment they are experiencing or about their was used for the drapes that covered afrom casket. hisAlthough org dies. the chest, ano anizations oped me ther cow bullet the wounde have dev asu discomfort due boy gav we continue to drape coffins—most memorably with the eld man tice guidel rement tools and e to their cancer diagnosis or its treatment. a bottle of to drink ines for pracand a whicases In many flag—the drape is no longer referred to this term. ske they may simply assume that the discomhelping hisby teeth. I’m knife to bite betwee y providers the purpose of nwith the disease.” However, with the imeffectively age pain The World Health Organizationwas modified its sure orig-back infort how peo associat the “comes manday this ple coped provements in medicine and the power of science,its it treatment. ed with cancer and inal definition of palliative care as quo follows: “Palliative with pain r to num The followi – lib them and pro ng articles d toquality doesn’t anymore. Do not wait for your patients vide you with care is an approach that improveshar the of life somethhave call bite on. ing to a wealth mation asso This is far him asking him to MAS back of e idea wrotfrom ised he kney, RN, BS, about their symptoms; be proacof patients and their families facingTod the ay problems asall pat t sank l.a discussion and guidel ciated with the inforhow surpr ien.tsI whto initiate hear Lillie D. 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, an me. whe atieHe at all mote tful care on he nd the nt uni r itand to bring to you inuum series. This the inp mati respo lege be to infor Lillie sure t or be me privi the a for of tak D. my tha clin is all ir was t Shoey Cont en to t all doctor, are ic visi rated ckney, I reite t with t the long journ Cancer Care options, RN, phon cancer pat of us address wit enaskede. to BS, MA talk by abou we sure Conquering the es specifically on hospice Hopee-pain mea me com h our ����� �Green Hill Healthcare Communications, LLC ien her toldplete a ts the pai toget S focus experienci of whethe ment toolhad had endured n they are rtant to read. thaand issue, which wife impo his t ng ly 30. pro r vital and age the vid he at y are presen es al diagn imp to relieve ve to be gree. Pat e exposis initisom is one I belie tly in ressofion it. Pain stea lement ways herpain here will be ients hav clini essed since her addr tim n , and to ls iptio e trouble on his descr e, psycho what to circ what de- ness,phy fully, concepts and better ways of it sical end logical wel away social Base,d however, inte ed alert tuaI lly abs urance and can pain was le (a happy face rpreting ly ill. adopted as newterminally ill cancer ition and limit make qua l-being, and ent for som bad in the cond a ver calor grave and y thatface lity of life cause the she) ifwas mornin ntsad supporting our families. g but theirthe doctor adequate trea e patients. Accur y virevide not their so I thou ate assessm tment for ment nee doctor. Fur took a pain pillwas ng an nowght patients and befohim that bad effectiv ent self thatthehecan d to be prioriti al years ago getti He himbeviewed by thermore, is thistold re com essetod see I recall sever es for all e pain manageBill. distring cer info o his ed s the any s fiel a nam rma after w one r d. of tion actu a man us workin during the and sometim to linge I feel con net and difficult ally e-mail from it Som g in ir visi d t? re- this next fident you es foun via the Inter etim will find Certainly it is not. ion regaris,ding pro had found me his young is ing and con hevok these arti one of the brief conversat es itthat whatwill stating that tain cer me cles And to ing grea pat . assi e cancan tho ients is the valu test fearfor wrot Mary a st you in breasstt s exp metastatic brea reassessing able information ught fear of painstep welbut ressher is not a drug oncan l(He ed by as dev ng wife, Mary, had gressed to her liver, your curren that andplaci now sufferin pro d- hospice. future pat eloping more effe calle g and cer that had . She was ctive way t patients as ei ients hav the special program before eis to hel and now brain d this term fectively manage e quality of life Lilliesleeping lungs, bone, had not hear n to explain some of by having p your d. Q hospital and D. Shockney, RN pain efI bega , BS, MAS currently in the awake, confused at © 201)3As care, he ther. ice Gre was hosp she en RN, of , Hill fits Healthc kney more than “had still my the key bene and are“Lill Lillie D. Shoc Comie, weight, but said, municat t until BS, MAS times, losing chemotherapy he fou got very upse 8 years old. I ions, LLC doctor rth issue of Conqu 2 sons, 6 and been receiving die. We have then told him that she wrote that the Colast erincann g theotCa wife the ntinuum ser yesterday.” He e.” I nce alonre s with thiadd care of her for nin I would work meet himies rescann ot raise themr Caice ses Tre e and situ staff and who had taken d him to com g Thro and atio m atm hosp said o m n. r He i that ugh . e ent h t Th but aske g steps n the Cancewould die Plane goa losi Follow about next n ren for the 4 years had r Ca preCpaont hile ds who l of the team re these child room to talk ing are 2 er for a wicle andy frien outcom is optimal him tore inuum.ly members rap morning in her onthe t would ling key art imes. role medical asized the im identify fami the cologis taking place,s to pro of the emph vidhim s were help e ins boys. I Th ere clin that usually ad discussion are – adight intthese ical pha that types gistofas e o the duck rmacolwoul doctor said in a row nowsom d help him raise s ly a me . The cal whenever these was very oo brief gh considerations mb all to g bee Tho Thou ng er wasthe “goin he plin that have absentugh mutoltidisciportance of getti will, power of attorney,netc. ing, so he of but can no but this time no ary this historiier work tea on that long m zed tive, went lon theng col ger remain , he reali andrkin vance direc husbwo treatments were to izz.”

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• Palliation • Pain management • Hospice care • Treatment planning • Survivorship care • Biosimilars in supportive care

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Introduc tion to O ncology Pain Ma nagem ent

CONTIN

UU

FOURTH

ISSUE IN THE 2013 SERIES SE CPa N nts D ANN ort to Otie pp Su UAL al itic ing Cr vid Pro : re Hospice Ca s and Familie

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Conquering t Cancer Carehe CONTI

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Personaliz ed Treatm ent Plann ing

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. And the is paper or ele re is a new ctronically prescriptio kle in the wrinn instructio – n treatment planni ns to be fille by the pha – what wil rmacologi l this treatme ng process st or pharma d These ind nt cost? Wi patients hav cist. ividuals, ll e to experts in managem their treatme pay out of pocket for drug ent, i nt? Is the cost of trea mization, are nteraction, and opt ment worth it tintegral to the clinica the oncolo care team. to be achiev l outcomes gy You will ed? No pat soon read ients wan learn why. lea Lillie ve their fam D. and Shockney, t to ily in dee RN, although we p debt, and And speaki BS, MAS have entere ng of the tea that the pat d an excitin era of person m, it is crit ient, and cer g ically imp aliz ortant tain family cases, be con of these new ed medicine, the cos compared members in t sidered me drugs is inc with treatme some mbers of the ning team. redibly hig nts we hav to in the We should h treatment e been acc past. Even not be doi plan we must be nustomed prior treatme ng things to bee doing things n dau nting from a patient; nt regime patients, of with a pat a cost perspe ns have ient. Thoug Everyone course, are ctive. wan h the not experts many have the right trea ts to make sure tha on oncolo desperatel t the patien gy care, y tried to tment at the sort by tur t gets become ex way. Now ning to the right time perts off a clinicians Internet and and in the for themse mu right trying to det treatment’s st realize tha lves what treatment sake is nev t treatment would be bes ermine er wise and Thoughtf for t for their ul decisio not the ns about mission. and patien treatm ts, oncolo gists, pharma ent are a must, cologists, palliative © 2013 Gre en Hill Hea lthcare Com munication s, LLC

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www.PersonalizedMedOnc.com PMO A-SIZE CCC_081513

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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GLOBAL BIOMARKERS Clinical Approaches CONSORTIUM to Targeted Technologies ™

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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