PMO june 2013 by The Oncology Nurse

June 2013 Volume 2 • Number 4 A Peer-Reviewed Journal

The official publication of

Global biomarkers Consortium Clinical Approaches

PM O TM

to Targeted Technologies

Personalized Medicine in Oncology TM

PANCREATIC CANCER A Path Toward Pancreatic Cancer Predictive Biomarkers……........................Page 182

INTERVIEW WITH THE INNOVATORS Personalized Medicine and Value: The Intersection of Science and Financial Viability. An Interview With Experts in Healthcare Strategy.....................................................Page 192

CONTINUING MEDICAL EDUCATION Faculty Perspectives: Recent Advancements in the Treatment of Multiple Myeloma. Proceedings From a Post-IMW Roundtable................................................Page 196

COLON CANCER Gene Profiling in Colon Cancer: How to Integrate Profiling Into Practice................. Page 204

also in this issue… • The Last Word by Robert E. Henry.........Page 224

Implementing the Promise of Individualized Cancer Care TM

In partnership with

Important Safety Information WARNINGS AND PRECAUTIONS: • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%),

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

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (N=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (N=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (N=102) and Study 2 (N=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (N=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (N=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%). DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

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

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

RECHARGE THE POSSIBILITIES

www.istodax.com Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

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Only

ISTODAX® (romidepsin) for injection For intravenous infusion only

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1. Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)

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The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug. 2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2. • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2. • Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2. 2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)]. 5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)]. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)]. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients

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

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Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin® (a registered trademark of BristolMyers Squibb Pharma Company) or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors. Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort. 7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus. Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were Cosmos Communications

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Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

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

noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification. 8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)] 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable. 12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of romidepsin on the heart-rate corrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8, 10 or 12 mg/m2 as a 1–hour infusion. Patients received premedications with antiemetics. No large changes in the mean QTc interval (> 20 milliseconds) from baseline based on Fridericia correction method were detected in the trial. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded because of the limitations in the trial design. Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6 hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2012 Celgene Corporation. All Rights Reserved. U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBAXPI.004/PPI.004 03/12

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

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17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)]. • Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)]. • Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2]. • Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)]. • Use in Pregnancy If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling. [See Warnings and Precautions (5.5)]. • Patients should be instructed to read the patient insert carefully.

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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PANCREATIC CANCER A Path Toward Pancreatic Cancer Predictive Biomarkers

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INTERVIEW WITH THE INNOVATORS Personalized Medicine and Value: The Intersection of Science and Financial Viability. An Interview With Experts in Page 192 Healthcare Strategy PMO talks with John Hennessy of Sarah Cannon, Pamela Morris of Zitter Health Insights, and Randy Vogenberg, PhD, RPh, of the Institute for Integrated Healthcare about cost/value challenges presented to payers.

CONTINUING MEDICAL EDUCATION Faculty Perspectives: Recent Advancements in the Treatment of Multiple Myeloma. Proceedings Page 196 From a Post-IMW Roundtable

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Trouble at the Beginning: Diagnostic Acumen and the Relentless Search for Red Flags Page 224 Robert E. Henry Mr Henry discusses the use of diagnostics to find the red flags that will prevent appropriate personalized care.

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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.

Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano

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.

Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen

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

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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.

Personalized Medicine

Oncology

June 2013

therascreen® companion diagnostic For in vitro diagnostic use

Proven clinical utility in colorectal cancer

Benefits of the therascreen KRAS RGQ PCR Kit: ■ The only FDA-approved KRAS test for IVD use ■ Treatment effective in patients with KRAS mutation-negative (wild-type) tumors ■ Approval based on Phase III clinical trial data with ERBITUX® ■ Standardized assay for reproducible results

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■ Easy workflow with automated reporting Visit www.qiagen.com/therascreen for more information Trademarks: QIAGEN®, therascreen® (QIAGEN Group). 03/2013, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

Sample & Assay Technologies

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

Personalized Medicine

Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida

Oncology

June 2013

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MDxHealth is regulated under the Clinical Laboratory Improvement Amendments (CLIA) and the College of American Pathologists as an accredited laboratory to perform high complexity clinical testing. The ConfirmMDx for Prostate Cancer test was developed and its performance characteristics determined by MDxHealth. This test is intended for use as an aid to clinicians for patient management decisions for the need to perform repeat biopsy on patients with a previous histopathologically negative biopsy result (benign or HGPIN, but excluding ASAP) within the past twenty-four months and high-risk clinical factors for occult prostate cancer. Use outside of this indication has not been validated by MDxHealth. The test results should be interpreted in conjunction with other laboratory and clinical data available to the clinician and relevant guidelines in the decision for repeat biopsy. References: 1.Resnick MJ et al: Repeat prostate biopsy and the incremental risk of clinically insignificant prostate cancer. Urology. 2011 Mar;77(3):548-52. doi: 10.1016/j.urology.2010.08.063. 2. Stewart G et al.: Clinical Utility of an Epigenetic Assay to Detect Occult Prostate Cancer in Histopathologically Negative Biopsies: Results of the MATLOC Study. J Urol (2013), 189, 1110-1116. 3. Henrique R et al.: Epigenetic Heterogeneity of High-Grade Prostatic Intraepithelial Neoplasia: Clues for Clonal Progression in Prostate Carcinogenesis, Mol Cancer Res 2006;4:1-8.

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Letter From the Board

Personalized Medicine in the Public Arena: Managing Expectations Dear Colleague,

ngelina Jolie’s recent surgery might be termed “the double mastectomy heard ’round the world.” It certainly holds important lessons for physicians, the public, and for your product’s market access. Ms Jolie’s treatment decision, a response to the dreaded mutation of the BRCA gene that gave her a 90% chance of developing breast cancer, can be expected to draw more women to request a BRCA screening – and to induce the public at large to request personalized medicine (PM) healthcare for their cancer. This “populist medical urge” is a potent force. Managed properly, it can do much to advance the utilization of PM strategies, services, and Sanjiv Agarwala, MD products. Poorly managed, it can twist this newfound awareness of the healing power of PM into a shortsighted attempt to replicate a star’s experience. As oncologists, we need to direct it. Enter Personalized Medicine in Oncology (PMO). We offer the practicing oncologist practical translational knowledge on PM screening, diagnostics, and treatment that helps channel society’s enthusiasm for PM’s benefits. Celebrity health crises like this point a double-edged sword at the oncologist. It increases public demand for PM, but there are those who will try to “play doctor” and determine their clinical strategy unilaterally. PMO keeps oncologists informed and prepared to deal with an anxious public, preventing misuse of PM, deflecting populist attempts to control diagnostic and treatment measures. Each issue of PMO delves into the wide array of the new medicine that is personalized medicine. This knowledge is real power, preparing oncologists to treat each patient according to an enriched knowledge base and stimulating discourse with patients on the application of PM advances. This will foster a healthy interest by the public in PM strategies and practices in oncology, channeling the energy flowing from celebrity health events. Thank you for being part of our reading community, and as always, we hope this issue of PMO empowers you to best serve your patients. Sincerely,

Sanjiv Agarwala, MD St. Luke’s Hospital PMO Board Member

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2013 ASCO Annual Meeting

Anti–PD-L1 Drug Achieves Response in Variety of Tumors Alice Goodman

he engineered PD-L1–targeted antibody shows impressive tumor shrinkage rates in several types of cancers that had progressed on several lines of previous therapy. In a phase 1 study, the novel agent demonstrated safety and durable responses in non–small cell lung cancer (NSCLC), melanoma, and kidney, colorectal, and gastric cancers. The best responses were seen in NSCLC, melanoma, and kidney cancers. The study was presented at the 2013 ASCO Annual Meeting. The drug, MPDL3280A, manipulates the immune system by blocking an immune checkpoint. Cancer cells frequently express the PD-L1 protein, allowing them to evade the immune system. By blocking the PD-L1 protein, the cancer cells become vulnerable to attack by T cells because they are now recognizable.

The phase 1 trial enrolled patients with a variety of incurable or metastatic solid tumors. MPDL3280A was given every 3 weeks. “MPDL3280A was well tolerated, with no dose-limiting toxicities and no significant side effect, particularly pneumonitis, which is of concern. Immune-related adverse events were uncommon,” explained lead author Roy Herbst, MD, Chief of Medical Oncology at Smilow Cancer Hospital at Yale-New Haven, CT. “Tumor PD-L1 expression appears to be associated with response to this agent. Further monotherapy and combination therapy studies are planned.” The phase 1 trial enrolled patients with a variety of incurable or metastatic solid tumors. MPDL3280A was given every 3 weeks. Response was assessed by CT scan every 6 weeks.

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Safety was assessed in 171 patients. “No maximum tolerated dose was seen. We were able to keep giving higher doses of the drug. There were no dose-limiting toxicities and no treatment-related deaths,” Herbst stated. Grade 3 or 4 adverse events were reported in 43% of patients. Only 1 patient withdrew from the trial due to a treatment-related adverse event (elevated ALT levels). Looking at tumor shrinkage, response was achieved in 29 of 140 patients, for an overall response rate (ORR) of 21%. In tumors that expressed PD-L1, ORR went up to 36%, while ORR was 13% in tumors that tested negative for PD-L1 expression. “Responses were seen in tumors without the PD-L1 protein. Responses occur quickly and are durable,” Herbst said. At the time of the ASCO 2013, 26 of 29 responses were ongoing. Durable responses were seen in melanoma, renal cell carcinoma, and head and neck, colon, and bladder cancers. Responders were on treatment from 3 to 15 months. The phase 1 study has been expanded to include 275 patients, some of them with hematologic cancers. Further study is planned, including combination therapy with targeted agents. “This study shows that productively manipulating the immune system can achieve a response rate of 21%, lasting as long as a year in tumors that progressed on previous treatment. The clearest indications of activity in this phase 1 study are in NSCLC and melanoma, as well as in patients with tumors testing positive for the PD-L1 marker. Maybe in the future we can develop biomarkers for tumors sensitive to this approach. This approach of unblocking this checkpoint in the immune system and allowing it to ramp up is the beginning of a new chapter in cancer therapy,” stated ASCO President-Elect Clifford A. Hudis, MD. u

Personalized Medicine

Oncology

June 2013

2013 ASCO Annual Meeting

Combination Immunotherapy Shows Promise in Advanced Melanoma Alice Goodman

ombination therapy with ipilimumab and nivolumab achieved remarkable responses in a phase 1 trial of patients with aggressive advanced melanoma. Durable tumor shrinkage was observed in about half the patients. “The complete and near-complete responses we are seeing are unprecedented for an immunotherapy in melanoma. We are particularly impressed that the drugs work together so well,” stated lead author Jedd D. Wolchok, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York City. “This study shows that combining immunotherapies has the potential to improve upon single-agent immunotherapy,” he added. Ipilimumab is a standard treatment option for advanced melanoma. Nivolumab is a novel PD-L1 antibody that has shown promising activity in melanoma and other cancers. Both drugs target immune system “checkpoints” – CTLA-4 in the case of ipilimumab and PD-L1 in the case of nivolumab – by releasing these “brakes” on the immune system, activating T cells to attack the cancer. The average overall survival in metastatic melanoma is 10 to 14 months, Wolchok said. Previous studies showed an objective response rate of 11% with ipilimumab and 41% with nivolumab when used separately in advanced melanoma. In this phase 1 trial, patients with inoperable stage III and IV melanoma treated with up to 3 prior lines of therapy were assigned to 6 different treatment arms. The results presented at a pre-ASCO press cast and then reported at the ASCO Annual Meeting were based on 3 arms in which concurrent treatment was given with the 2 drugs to 52 patients. Sequential treatment was used in 3 arms, and those responses were not reported. The objective response rate, defined as a reduction of tumor volume of at least 50%, was 53% with concurrent treatment, which is substantially higher than with

Volume 2 • No 4

either drug alone. About 90% of responses continued as of February 2013. Wolchok said that melanoma was controlled in about 65% of patients if those with stable disease were included. Combination therapy with the maximum dosages of both drugs achieved tumor shrinkage of ≥80% at 3 months in 41% of patients. Both treatments had side effects that were manageable with standard algorithms for each medication alone, Wolchok said.

Combination therapy with the maximum dosages of both drugs achieved tumor shrinkage of ≥80% at 3 months in 41% of patients. Side effects were more frequent with the sequential therapy than with the concurrent therapy, he said. The most common adverse events were asymptomatic elevated enzymes in the liver and pancreas. Rare side effects included inflammation of the colon, eyes, or lungs, all of which were reversible. Further studies of the concurrent regimen versus nivolumab versus ipilimumab are ongoing in advanced melanoma. The combination is also being studied in non–small cell lung cancer and renal cell carcinoma. “This is an exciting study, showing great improvement and progress. The combination of 2 immunotherapies led to rapid and profound lasting tumor shrinkage. Ninety percent of responders are still responding. This has not been seen with immunotherapy before. This study of the combination of 2 drugs that release the brakes of the immune system is proof of principle that 2 immune agents can change the paradigm of treating melanoma,” said ASCO President Sandra Swain. u

www.PersonalizedMedOnc.com

June 2013

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2013 ASCO Annual Meeting

First-in-Class PI3K Inhibitor Shows Remarkable Phase 1 Results in CLL Alice Goodman

first-in-class PI3 kinase (PI3K) inhibitor achieved dramatic responses in a phase 1 study of heavily pretreated relapsed/refractory chronic lymphocytic leukemia (CLL). Idelalisib (GS-1101) produced rapid and durable tumor shrinkage in about half the patients who received the drug. These results were reported at a preASCO press cast and at the 2013 ASCO Annual Meeting. “This is a dramatic finding. The expected time to progression with a sixth-line treatment in this setting would be 6 to 12 months,” said lead author Jennifer Brown, MD, PhD, Director, Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, Boston, MA.

Idelalisib was well tolerated. The most commonly reported adverse events included asymptomatic elevation of liver enzymes, diarrhea, and rash. “There are currently few effective treatment options for relapsed CLL. Patients go into remission, but the time between remissions gets shorter and shorter. It appears that we are now reaching a point in CLL where we will have several agents that are very effective. Drugs like idelalisib are probably going to change the landscape of the disease in the next few years,” Brown commented. Idelalisib is a potent selective blocker of PI3K-delta, a subtype of PI3K protein that is overexpressed in B-cell lymphoma and promotes tumor growth. Idelalisib joins ibrutinib as a potential new treatment that could change outcomes in this disease. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is in phase 3 testing, and FDA approval is expected soon. The phase 1 study enrolled almost 200 patients with previously treated hematologic malignancies. Brown presented results from 54 patients with CLL. Median age was 63 years; 70% of patients had bulky lymphade-

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nopathy; 70% had refractory disease; 91% had unmutated IGHV; 24% had del(17p) and/or TP53 mutation; 28% had del(11q); and 17% had a NOTCHI mutation. Median number of prior lines of therapy was 5. Idelalisib was given orally in doses of 50 to 350 mg once or twice a day continuously in 28-day cycles. The average duration of treatment with idelalisib was 9 months. Idelalisib was well tolerated. The most commonly reported adverse events included asymptomatic elevation of liver enzymes, diarrhea, and rash. Treatment discontinuation due to treatment-related events was seen in 7%. Response (tumor shrinkage) was observed in 30 of 54 patients for an overall response of 56%; 2 patients had a complete response and 28 patients had a partial response. Stable disease was observed in 21 patients (39%). Forty-four patients (81%) had a lymph node response. Idelalisib achieved deep and durable responses independent of the presence of del(17p) or TP53 mutation, both prognostic of poor risk. Regardless of the dose, median progression-free survival was 17 months, and median duration of response was 18 months. “We also saw a decrease in symptoms of CLL and improvement of baseline cytopenias. Low blood cells are common at the start of treatment,” she said. The dose of 150 mg bid was selected for phase 2 and 3 studies. Phase 3 trials of idelalisib in combination with rituximab or bendamustine/rituximab are now in progress. “This drug represents another exciting and early success in precision medicine. In heavily refractory patients and older patients, this is a great response, with an overall response rate of 56%. Even more striking is progression-free survival of 17 months. Two patients are still in remission. This is incredible. We may soon have a new alternative to chemotherapy and a simpler oral treatment that improves patient quality of life,” said ASCO President Sandra Swain, MD. u

Personalized Medicine

Oncology

June 2013

2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

July 26-28, 2013

Hyatt Regency La Jolla • San Diego, California PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.

DESIGNATION OF CREDIT STATEMENTS SPONSORS

FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am – 8:00 am

Symposium/Product Theater/Exhibits (non–CME-certified activity)

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies • Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway • Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits (non–CME-certified activity) 1:00 pm – 1:15 pm

BREAK

1:15 pm – 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies • Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients • Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies • Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

The Medical Learning Institute Inc designates this live activity for a maximum of 13.0 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.

www.CutaneousMalignancies.com WCMC2013ConferenceA_Ad_60313

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA*

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

PHYSICIAN CREDIT DESIGNATION

Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits (non–CME-certified activity)

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Review of Saturday’s Presentations and Preview of Today’s Sessions

8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician • Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies? 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits (non–CME-certified activity) 1:00 pm – 1:15 pm

BREAK

1:15 pm – 2:45 pm

General Session V: “Hot Data” — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

Pancreatic Cancer

A Path Toward Pancreatic Cancer Predictive Biomarkers Joshua D. Rosenberg, MD Clinical Fellow, Hematology/Oncology Scripps Clinic San Diego, California Darren Sigal, MD Division of Hematology/Oncology Scripps Clinic Medical Group San Diego, California

Key Points • After years of clinical investigations, important progress is finally being made in the treatment of pancreatic cancer • Single-agent gemcitabine is yielding to combination therapies, such as FOLFIRINOX, and more recently the combination of gemcitabine and nab-paclitaxel • Oncologists who treat patients with pancreatic cancer will be faced with the dilemma of drug sequencing

n 2012, pancreatic ductal adenocarcinoma afflicted an estimated 43,920 people in the United States, and approximately 37,390 people died of this disease. Despite being only the tenth most common cancer, it is the fourth most common cause of cancer death.1 About 20% of patients will present with localized, resectable pancreatic cancer. Although adjuvant chemotherapy with gemcitabine or 5-fluorouracil (5-FU) confers a small survival advantage, the vast majority of these patients will relapse and die of their disease. The other 80% of patients will have either de novo metastasis or locally advanced cancer making potentially curative resection impossible.2 Overall, only about 4% of patients will be alive and disease free at 5 years.3-5 It is clear that pancreatic cancer represents an urgent unmet medical need for more effective therapies.

Two important developments that may finally alter the natural history of incurable pancreatic cancer have been reported over the past couple of years. In a phase 3 trial, patients randomized to FOLFIRINOX (combination bolus and infusional 5-FU, irinotecan, and oxaliplatin) had significant improvements in median overall survival (OS) (11.1 vs 6.8 months; P<.001) and overall response rates (32% vs 9%; P<.001) compared with single-agent gemcitabine, respectively.6 Recently presented at the 2013 Gastrointestinal Cancers Symposium was a large phase 3 trial (MPACT) that randomized patients to combination nab-paclitaxel and gemcitabine versus single-agent gemcitabine. Patients in the combination therapy cohort had improved median OS (8.5 vs 6.7 months; P=.000015) and overall response rates (23% vs 7%, P=1.1×10–10).7 These are

Dr Rosenberg received his medical degree from the University of California, Irvine, and is currently practicing as a third-year fellow in the Division of Hematology/Oncology at Scripps Clinic. Dr Sigal received his medical degree from the University of California, Los Angeles, and is currently practicing in the Division of Hematology/Oncology at Scripps Clinic Medical Group. He is Principal Investigator of the Pancreas and Biliary Cancer Program at Scripps Clinic.

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clinically meaningful improvements over published reports of single-agent gemcitabine or the combination of gemcitabine and erlotinib.8,9 With the advent of potentially multiple effective therapeutic regimens, incorporation of pancreatic cancer predictive biomarkers into clinical care may enable the selection of the most effective therapy for a specific tumor profile. Predictive, as opposed to simply prognostic, biomarkers are key for achieving this goal. A prognostic biomarker predicts outcome differences independent of any intervention, whereas a predictive biomarker predicts outcome differences based on a specific intervention, making the latter central for determining therapy. Some of the more promising biomarkers include human equilibrative nucleoside transporter 1 (hENT1), secreted protein acidic and rich in cysteine (SPARC), deoxycytidine kinase (dCK), and ribonucleotide reductase subunit M1 (RRM1) (Figure). Each of these proteins may be integral for chemotherapeutic agent uptake, metabolism, or cytotoxicity, making them putative predictive biomarkers. Solid evidence supporting a biomarkerâ&#x20AC;&#x2122;s predictive value usually follows a pathway beginning with preclinical studies (in vitro, ex vivo, animal models) and clinical prognostic data before predictive data can be generated. These 4 biomarkers are well along this path, and we feel that an overall review of them is now appropriate.

a pancreatic tumor xenograft mouse model that used 5-FU to upregulate hENT1, a significant cellular growth inhibition was noted when gemcitabine was administered subsequently.16 Interestingly, a phase 3 trial did not show improved OS among patients randomized to combination capecitabine, an oral 5-FU prodrug, and gemcitabine compared with gemcitabine alone, although outcomes according to hENT1 status were not reported.17 As will be seen with all 4 biomarkers evaluated in this article, none of the clinical studies evaluating the prognostic or predictive value of hENT1 utilized consistent hENT1 assays or cutoff values. Although similar antibodies were employed for immunohistochemistry (IHC), different scoring systems were utilized â&#x20AC;&#x201C; one trial used a 0 to 2 scale based on adjacent islet of Langerhans cell and lymphocyte staining, while others used a 0 to 3 scale based on the percentage of cells at each staining level. Another study used reverse transcription-polymerase chain reaction (RT-PCR) to determine high and low values according to a ratio with the glyceraldehyde-3-phosphate dehydrogenase reference gene.18-25

Patients with high hENT1 levels had a significantly longer median OS versus those in the lower expression subgroup at 25.7 versus 8.5 months.

hENT1 Gemcitabine is a hydrophilic pyrimidine nucleoside analogue that requires specialized membrane nucleoside transporter proteins to efficiently cross the plasma membrane and enter cells.10 hENT1 is found in most cell types and mediates concentration-dependent gemcitabine cellular uptake.11,12 Gemcitabine levels are increased in pancreatic cancer cell lines incubated with gemcitabine that display high hENT1 expression.13 In vitro gemcitabine toxicity is determined by hENT1 expression and activity patterns. High hENT1-expressing cell lines incubated with dipyridamole, a potent inhibitor of hENT1 activity, were resistant to gemcitabine due to its reduced cellular uptake.14,15 Conversely, in

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Several retrospective analyses have correlated pancreatic cancer patient outcomes to hENT1 expression. However, because all patients in these studies received gemcitabine and no untreated control groups existed, they can only support the role of hENT1 as a prognostic marker. RT-PCR analysis for hENT1 expression was performed on 102 microdissected pancreatic cancer samples from patients with localized to metastatic disease, and all patients were treated with gemcitabine.18 Patients with high hENT1 levels had a significantly longer median OS versus those in the lower expression subgroup at 25.7 versus 8.5 months (P<.001).18 Additionally, patients with high versus low hENT1

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expression had a statistically significant advantage when comparing disease-free survival (DFS) (20.4 vs 9.3 months) in the adjuvant setting and time to progression (12.7 vs 5.9 months; P=.02) in the metastatic setting.18 Multivariate analysis, comprising adjuvant or palliative treatment, tumor grade, cytidine deaminase expression, and hENT1 expression, confirmed the prognostic significance of hENT1 expression as an independent factor associated with survival.18 Two additional retrospective studies measured hENT1 by IHC in the metastatic and adjuvant setting and confirmed the prognostic power of hENT1.19,20 However, a more

These findings call into question whether drug delivery is the mechanism of action for the putative predictive value of low hENT1 status for gemcitabine therapy.

compared with those who did not receive gemcitabine. Patients with low hENT1 did not benefit from gemcitaÂ bine.17 The only prospective study (LEAP) was a phase 2 trial that randomized 360 patients to gemcitabine or CO-101, a gemcitabine-lipid conjugate that is able to enter cells independent of hENT1.25 Inclusion criteria required patients to have metastatic pancreatic cancer and possess tumors with low hENT1 expression. A recent company media release indicated that no difference in survival was found between patient cohorts.26 These negative findings call into question whether drug delivery is the mechanism of action for the putative predictive value of low hENT1 status for gemcitabine therapy and reinforce the need for inclusion of both biomarker-positive and biomarker-negative cohorts in prospective, randomized trials to better understand the impact of the markers in question.

SPARC recent study that randomly selected 95 specimens from patients who had undergone pancreaticoduodenectomy was unable to correlate hENT1 expression to survival.21 Cross-study comparisons are always difficult, especially for small retrospective trials, but this trial does highlight the importance of developing optimal hENT1 detection assays, defining threshold hENT1 expression criteria, and contemplating the possibility that its prognostic value may differ in the adjuvant or metastatic setting. Two retrospective studies raised the possibility of hENT1 as a predictive biomarker. Farrell and colleagues22 evaluated hENT1 expression by IHC from 229 of 538 patients who had undergone surgical resection. These patients were enrolled in RTOG 97-04,23 a phase 3 adjuvant study evaluating the impact of adding gemcitabine to adjuvant 5-FU chemoradiation on survival. High hENT1 expression was associated with both improved OS and DFS (P=.01 and P=.04, respectively) only in patients who received gemcitabine.22 Another study analyzed hENT1 by IHC in 434 specimens from patients who had also undergone curative surgery.24 Patients with high hENT1 expression who also received adjuvant gemcitabine had improved OS (P<.001)

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Secreted protein acidic and rich in cysteine (SPARC), also referred to as osteonectin, is a calcium-binding glycoprotein involved in cell-matrix interactions. SPARC is involved in many biological processes including cellular differentiation, tissue remodeling, cell migration, cell invasion, morphogenesis, and angiogenesis.27-29 SPARCnull mice have reduced pancreatic tumor cell apoptosis and enhanced tumor progression, demonstrating a growth inhibitory function.30,31 SPARC is generally expressed in normal pancreatic tissue. However, aberrant promoter hypermethylation is likely responsible for loss of SPARC expression within pancreatic cancer. SPARC overexpression is actually induced in the peritumoral stromal fibroblasts and extracellular matrix immediately adjacent to the cancer.32-34 The clinical importance of SPARC in pancreatic cancer was first suggested in a retrospective study of 299 pancreaticoduodenectomy specimens that were stained for SPARC by IHC. Patients whose pancreatic cancer peritumoral fibroblasts expressed SPARC had a significantly worse median OS than those whose peritumoral stroma did not (15 vs 30 months; P<.001).35 An albumin-bound nanoparticle form of pacli-

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taxel, nab-paclitaxel, binds SPARC via albumin, potentially directly delivering paclitaxel to tumors with increased SPARC expression.36 SPARC has therefore been postulated to be a potential predictive biomarker for nab-paclitaxel. The phase 1/2 trial that determined the maximum tolerated dose of combination nab-pac litaxel and gemcitabine included a preplanned subgroup analysis of SPARC expression by IHC scored by an exhaustive methodology.37 Patients with high SPARC expression had a significantly prolonged median OS compared with those with low SPARC expression (17.8 vs 8.1 months; P=.0431).37 In contrast to the previously described retrospective study showing that peritumoral SPARC expression correlated with worse outcome, this trial showed that patients with increased peritumoral SPARC actually had improved survival. This discrepancy may result from inconsistencies in detecting SPARC expression. Alternatively, this phase 1/2 trial was meticulous in determining SPARC expression, suggesting that nab-paclitaxel may more effectively deliver gemcitabine to the tumor, overcoming the deleterious impact of SPARC overexpression, and reinforcing the possibility that SPARC is a predictive biomarker for benefit from the combination of nab-pac litaxel and gemcitabine. A randomized phase 3 trial of the combination of nab-paclitaxel and gemcitabine was recently reported at the 2013 Gastrointestinal Cancers Symposium, but SPARC analysis was not included.7 A more definitive view of the predictive value of SPARC will emerge when the data are released.

dCK Deoxycytidine kinase (dCK) is an intracellular enzyme that serves as the rate-limiting step in the phosphorylation of gemcitabine to its active metabolites, gemcitabine monophosphate, diphosphate, and triphosphate.38 Overexpression of dCK has demonstrated increased gemcitabine sensitivity in various solid tumor cell lines, including breast, non–small cell lung, colon, ovarian, head and neck, and pancreatic cancers.39,40 Human colon carcinoma xenografts transfected with the dCK gene resulted in increased gemcitabine tri-

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phosphate cellular accumulation, prolonged elimination kinetics, and potentiated an in vivo tumor response to gemcitabine.41 Accordingly, dCK downregulation induced gemcitabine resistance in pancreatic cancer cells.42 Among the clinical studies evaluating the prognostic or predictive value of dCK, no consistency existed for either dCK assays or cutoff values. Even when a similar antibody was used for IHC, different scoring systems were employed – one trial used a 0 to 3 scale based on adjacent lymphocyte staining, and another used an intensity score defined as the product of a 0 to 2 scale and the percentage of cells at each staining level. Studies that used RT-PCR either correlated it to a β-actin control or determined high and low values according to the average RT-PCR value for the samples being evaluated.43-46

Overexpression of dCK has demonstrated increased gemcitabine sensitivity in various solid tumor cell lines, including breast, colon, ovarian, and pancreatic cancers. There is some evidence supporting the role of dCK as a prognostic biomarker. A retrospective review was performed on 44 specimens stained for dCK by IHC from patients treated with gemcitabine in the adjuvant or metastatic setting. Patients with high dCK expression had a significant improvement in median OS (22 vs 15 months; P<.009) compared with those with low dCK expression. High dCK expressers maintained their survival advantage even after adjusting for the progression-free survival (PFS) benefit after gemcitabine therapy (12 vs 10 months; P<.04).43 Prior to initiation of palliative gemcitabine in 35 patients with locally advanced pancreatic cancer, biopsies were obtained by endoscopic ultrasound fine-needle aspiration, and dCK mRNA was determined by RT-PCR. High dCK mRNA levels correlated to gemcitabine efficacy, while low dCK mRNA levels did not.44 Forty-five patients with localized pancreatic cancer who underwent curative

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resection as part of 2 separate phase 2 trials had tumor specimens stained for dCK by IHC. Median OS was 13.2 months for patients with low dCK expression and was not reached for those with high dCK expression (P=.0008). DFS was 6.3 months for low dCK expressers and 46.8 months for high dCK expressers (P=.0003). dCK expression was the only significant independent marker for OS and DFS in comparison with lymph node involvement, lymph node ratio, and greatest tumor diameter.45

Only patients with low RRM1 expression had a significant survival benefit, suggesting that low RRM1 is predictive for benefit from gemcitabine. Two retrospective studies report on dCK as a predictive biomarker. The expression of dCK by IHC was determined among 434 pancreatic cancer patients who underwent curative resection, with 243 of these patients administered adjuvant gemcitabine. Patients with high dCK who received adjuvant gemcitabine had improved survival compared with those who did not (hazard ratio 0.57; 95% CI, 0.41-0.78; P=.001). Patients with low dCK did not derive any benefit from gemcitabine (P=.66).24 RT-PCR was used to determine dCK mRNA levels in 40 patients who received adjuvant gemcitabine and 30 who did not after curative resection. High dCK mRNA expression was associated with a significantly longer DFS (P=.0067) in the gemcitabine-treated group.46

RRM1 Ribonucleotide reductase subunit M1 (RRM1) is the regulatory subunit of ribonucleotide reductase, an enzyme essential for cell survival that catalyzes the rate-limiting step of the DNA biosynthetic pathway, converting ribonucleoside diphosphate to deoxyribonucleoside diphosphate.47 RRM1 is the intracellular target of gemcitabine 5′-diphosphate, a phosphorylated

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metabolite of gemcitabine.48 RRM1 inhibition reduces the cellular concentration of deoxynucleoside triphosphates, blocking DNA synthesis.49 Gemcitabine resistance in non–small cell lung cancer and colon cancer cell lines was associated with increased RRM1 gene expression.50,51 Genetically modified lung cancer cell lines with increasing RRM1 expression displayed reduced gemcitabine efficacy.52 Finally, suppression of RRM1 expression by RNA interference restored gemcitabine sensitivity in a pancreatic cancer cell line.24 Increased RRM1 expression likely overcomes gemcitabine activity by increasing the deoxyribonucleotide triphosphate pool, competitively inhibiting the incorporation of gemcitabine triphosphate into DNA.53 RRM1 can also serve as a “molecular sink” by removing intracellular gemcitabine diphosphate, reducing the accumulation of active gemcitabine triphosphate.50 Again, the clinical studies evaluating the prognostic or predictive value of RRM1 had varying assays and cutoff values. Though similar antibodies were used for IHC, one study used a 0 to 3 scoring system based on the percentage of cytoplasmic staining, while the other was determined by automated quantitative analysis, a fluorescence-based IHC method. Studies that used RT-PCR correlated RRM1 mRNA to the reference genes β-actin or glyceraldehyde 3-phosphate dehydrogenase, or determined high and low values according to the average RT-PCR value for the samples being evaluated.44,54-56 Several reports support the prognostic value of RRM1 in pancreatic cancer. In a retrospective analysis, 68 pancreatic cancer patients underwent curative R0 resections with only 5 receiving adjuvant gemcitabine. Patients with low RRM1 expression determined by IHC had significantly decreased 3-year OS compared with those with high expression (46% vs 28%; P=.0196). Multivariate analysis noted that RRM1 expression was the only independent determinant of OS. Among the 23 patients treated with gemcitabine at disease recurrence, only patients with low RRM1 expression had a significant survival benefit (P=.0010), suggesting that low RRM1 is predictive for benefit from gemcitabine. However, this was still unclear since all patients were treated with gem-

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Figure. Pancreatic Cancer Biomarker Diagram b-p

axe

it acl

SPARC

extracellular compartment

gemcitabine

hENT 1

gemcitabine

dCK

gemcitabine monophosphate

NMPK gemcitabine diphosphate

RRMI

NDPK

Decreased precursors of DNA synthesis allowing increased gemcitabine triphosphate DNA incorporation

gemcitabine triphosphate

Incorporated into DNA causing cytotoxicity NMPK - nucleoside monophosphate kinase NDPK - nucleoside diphosphate kinase

dCK indicates deoxycytidine kinase; hENT1, human equilibrative nucleoside transporter 1; RRM1, ribonucleotide reductase subunit M1; SPARC, secreted protein acidic and rich in cysteine. citabine and an untreated control group did not exist.54 Another retrospective report reinforced these results. Eighteen pancreatic cancer patients who had curative resection and did not receive adjuvant gemcitabine were

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administered gemcitabine at the time of their recurrence. RRM1 mRNA levels were determined in the primary tumor specimens, and patients with low levels had significantly improved OS (P=.016).55

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Table. Pancreatic Biomarker Trials Biomarker Study

Analysis

dCK

Maréchal et al

Gemcitabine vs observation

Sebastiani et al

hENT1

RRM1

SPARC

Study Type

Prognostic

Predictive

Reference

IHC

243

Retro, NR

Yes

Gemcitabine

IHC

Retro, NR

Yes

Ashida et al

Gemcitabine

RT-PCR

Pro, NR

Yes

Maréchal et al

Gemcitabine

IHC

Retro, NR

Yes

Fujita et al

Gemcitabine vs observation

RT-PCR

Retro, NR

Yes

Giovannetti et al

Gemcitabine

RT-PCR

102

Retro, NR

Yes

Spratlin et al

Gemcitabine

IHC

Retro, NR

Yes

Maréchal et al

Gemcitabine/ radiation

IHC

Retro, NR

Yes

Fisher et al

Surgery

IHC

Retro, R

Yes

Farrell et al

Gemcitabine vs 5-FU

IHC

229

Retro, R

Yes

Maréchal et al

Gemcitabine vs observation

IHC

243

Retro, NR

Yes

LEAP trial

CO-101 vs gemcitabine

IHC

360

Pro, R

Akita et al

Surgery with gemcitabine at recurrence

IHC

Retro, NR

Yes

Nakahira et al

Gemcitabine

RT-PCR

Retro, NR

Yes

Valsecchi et al

Gemcitabine

RT-PCR + IHC

Retro, NR

Ashida et al

Gemcitabine

RT-PCR

Pro, NR

Von Hoff et al

Gemcitabine + nab-paclitaxel

IHC

Pro, NR

Yes

Infante et al

Surgery

IHC

299

Retro, NR

Yes

5-FU indicates 5-fluorouracil; dCK, deoxycytidine kinase; hENT1, human equilibrative nucleoside transporter 1; IHC, immunohistochemistry; NR, nonrandomized; Pro, prospective; R, randomized; Retro, retrospective; RRM1, ribonucleotide reductase subunit M1; RT-PCR, reverse transcription-polymerase chain reaction; SPARC, secreted protein acidic and rich in cysteine. However, these findings were not confirmed in 2 other studies. In a retrospective analysis of RRM1 expression by both IHC and RT-PCR in 94 patients with resected pancreatic cancer, RRM1 expression by either technique was not prognostic for OS, and low levels were not predictive for benefit from gemcitabine treat-

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ment.56 Finally, a small trial determined RRM1 mRNA expression by endoscopic ultrasound fine-needle aspiration in patients with locally advanced pancreatic cancer prior to the initiation of gemcitabine chemotherapy. RRM1 expression levels were not correlated with benefit from gemcitabine.44

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Conclusion After many years of fruitless clinical investigations, important progress is finally being made in the treatment of pancreatic cancer. For patients with an adequate performance status, single-agent gemcitabine is yielding to combination therapies, such as FOLFIRINOX, and more recently combination gemcitabine and nab-paclitaxel. For the first time, oncologists who treat patients with pancreatic cancer will be faced with the dilemma of drug sequencing. Unique mechanisms of action from these regimens, and future regimens, may be exploited to confer differential clinical benefits to specific patient cohorts. We have reviewed a selection of promising pancreatic cancer biomarkers that may eventually help guide clinical decision making and drug sequencing (Table). hENT1, RRM1, and dCK directly impact gemcitabine metabolism. SPARC is expressed in the pancreatic cancer peritumoral stroma and is targeted by albumin, potentially enhancing the activity of combination nab-paclitaxel and gemcitabine. Unfortunately, these potentially predictive pancreatic cancer biomarkers are not yet ready to be incorporated into patient care. Even for hENT1, the biomarker with the most clinically advanced data, most of the predictive data are from small retrospective studies with mixed adjuvant and metastatic populations. In the only prospective phase 3 trial, hENT1 expression was not predictive for benefit from a novel gemcitabine-lipid conjugate (CO-101), potentially undermining its predictive role for nongemcita bine therapies.26 SPARC is the only other biomarker with prospective data in a small phase 1/2 study that suggested elevated SPARC expression was predictive for benefit from the combination of nab-paclitaxel and gemcitabine.37 However, SPARC data were not included in the recent presentation of the phase 3 trial for this regimen, preventing any definitive conclusions of SPARC predictivity.7 The lack of large prospective trials validating these biomarkers should not necessarily impede their use. KRAS, the most important predictive colorectal cancer predictive biomarker, gained acceptance with only retrospective

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trials.57,58 However, these retrospective analyses should evolve from prospectively randomized trials of sufficient size and adequate control groups. A further difficulty in evaluating pancreatic cancer biomarkers, whether retrospectively or prospectively, is the general lack of consensus for accurate biomarker assays and inconsistent threshold values to determine positivity or negativity. Exacerbating this challenge is the limited amount of cancer tissue available from endoscopic ultrasound biopsies of the pancreatic tumor. This is particularly true in the locally advanced or neoadjuvant setting where large metastatic deposits are not available for core biopsies and the only tissue available is from an endoscopically attained fine-needle aspiration. However, the data that exist for these biomarkers are certainly hypothesis generating for their predictive role in pancreatic cancer. Future large retrospective analyses should ensure that inconsistencies in assays, threshold levels, and patient population and appropriately matched control groups are addressed. Also, randomized trials of new pancreatic cancer–targeted agents that prospectively incorporate reliable biomarker assays are the most promising approach for finally and definitively bringing predictive biomarkers into patient care. u

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12. Young JD, Yao SY, Sun L, et al. Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica. 2008;38:995-1021. 13. Garcia-Manteiga J, Molina-Arcas M, Casado FJ, et al. Nucleoside transporter profiles in human pancreatic cancer cells: role of hCNT1 in 2′,2′-difluorodeoxycytidine-induced cytotoxicity. Clin Cancer Res. 2003;9:5000-5008. 14. Mackey JR, Mani RS, Selner M, et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 1998;58:4349-4357. 15. Mori R, Ishikawa T, Ichikawa Y, et al. Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells. Oncol Rep. 2007;17:1201-1205. 16. Nakahira S, Nakamori S, Tsujie M, et al. Pretreatment with S-1, an oral derivative of 5-fluorouracil, enhances gemcitabine effects in pancreatic cancer xenografts. Anticancer Res. 2008;28:179-186. 17. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27:5513-5518. 18. Giovannetti E, Del Tacca M, Mey V, et al. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006;66:3928-3935. 19. Spratlin J, Sangha R, Glubrecht D, et al. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin Cancer Res. 2004;10:6956-6961. 20. Maréchal R, Mackey JR, Lai R, et al. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res. 2009;15:2913-2919. 21. Fisher SB, Patel SH, Bagci P, et al. An analysis of ERCC1, hENT1, RRM1, and RRM2 expression in resected pancreas adenocarcinoma: implications for adjuvant treatment. J Clin Oncol. 2012;30(suppl 4). Abstract 206. 22. Farrell JJ, Elsaleh H, Garcia M, et al. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009;136:187-195. 23. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcita bine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019-1026. 24. Maréchal R, Bachet J, Mackey JR, et al. Prediction of gemcitabine benefit after curative-intent resection of pancreatic adenocarcinoma using HENT1 and dCK protein expression. J Clin Oncol. 2011;29(suppl). Abstract 4024. 25. Business Wire. Clovis Oncology completes enrollment in pivotal LEAP trial of CO-101 versus gemcitabine in metastatic pancreatic cancer. www.businesswire.com/news/home/20120326005268/en/Clovis-Oncolo gy-Completes-Enrollment-Pivotal-LEAP-Trial. Accessed April 28, 2013. 26. Business Wire. Clovis Oncology announces negative outcome of CO101 in pivotal LEAP pancreatic cancer study. www.businesswire.com/ news/home/20121111005032/en/Clovis-Oncology-Announces-NegativeOutcome-CO-101-Pivotal. Accessed April 28, 2013. 27. Bradshaw AD, Sage EH. SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury. J Clin Invest. 2001;107:1049-1054. 28. Jacob K, Webber M, Benayahu D, et al. Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone. Cancer Res. 1999;59:4453-4457. 29. Brekken RA, Sage EH. SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol. 2001;19:816-827. 30. Puolakkainen PA, Brekken RA, Muneer S, et al. Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol Cancer Res. 2004;2:215-224. 31. Brekken RA, Puolakkainen P, Graves DC, et al. Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J Clin Invest. 2003;111:487-495. 32. Ueki T, Toyota M, Sohn T, et al. Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res. 2000;60:1835-1839. 33. Sato N, Fukushima N, Maehara N, et al. SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions. Oncogene. 2003;22:5021-5030. 34. Guweidhi A, Kleeff J, Adwan H, et al. Osteonectin influences growth and invasion of pancreatic cancer cells. Ann Surg. 2005;242:224-234.

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35. Infante JR, Matsubayashi H, Sato N, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol. 2007;25:319-325. 36. Von Hoff DD, Ramanathan R, Borad M, et al. SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) in patients with advanced metastatic pancreatic cancer: a phase I/II study. J Clin Oncol. 2009;27(suppl). Abstract 4525. 37. Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548-4554. 38. Mini E, Nobili S, Caciagli B, et al. Cellular pharmacology of gemcita bine. Ann Oncol. 2006;17(suppl 5):v7-v12. 39. Hapke DM, Stegmann AP, Mitchell BS. Retroviral transfer of deoxycytidine kinase into tumor cell lines enhances nucleoside toxicity. Cancer Res. 1996;56:2343-2347. 40. Kroep JR, Loves WJ, van der Wilt CL, et al. Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity. Mol Cancer Ther. 2002;1:371-376. 41. Blackstock AW, Lightfoot H, Case LD, et al. Tumor uptake and elimination of 2′,2′-difluoro-2′-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response. Clin Cancer Res. 2001;7:3263-3268. 42. Ohhashi S, Ohuchida K, Mizumoto K, et al. Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer. Anticancer Res. 2008;28:2205-2212. 43. Sebastiani V, Ricci F, Rubio-Viqueira B, et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res. 2006;12:2492-2497. 44. Ashida R, Nakata B, Shigekawa M, et al. Gemcitabine sensitivity-related mRNA expression in endoscopic ultrasound-guided fine-needle aspiration biopsy of unresectable pancreatic cancer. J Exp Clin Cancer Res. 2009;28:83. 45. Maréchal R, Mackey JR, Lai R, et al. Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma. Cancer. 2010;116:5200-5206. 46. Fujita H, Ohuchida K, Mizumoto K, et al. Gene expression levels as predictive markers of outcome in pancreatic cancer after gemcitabinebased adjuvant chemotherapy. Neoplasia. 2010;12:807-817. 47. Reichard P. From RNA to DNA, why so many ribonucleotide reductases? Science. 1993;260:1773-1777. 48. van der Donk WA, Yu G, Pérez L, et al. Detection of a new substrate-derived radical during inactivation of ribonucleotide reductase from Escherichia coli by gemcitabine 5′-diphosphate. Biochemistry. 1998;37:6419-6426. 49. Heinemann V, Xu YZ, Chubb S, et al. Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′,2′-difluorodeoxycytidine. Mol Pharmacol. 1990;38:567-572. 50. Davidson JD, Ma L, Flagella M, et al. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Cancer Res. 2004;64:3761-3766. 51. Bergman AM, Eijk PP, van Haperen VW, et al. In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as a major determinant. Cancer Res. 2005;65:9510-9516. 52. Bepler G, Kusmartseva I, Sharma S, et al. RRM1-modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small cell lung cancer. J Clin Oncol. 2006;24:4731-4737. 53. Plunkett W, Huang P, Searcy CE, et al. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol. 1996;23(suppl 10):3-15. 54. Akita H, Zheng Z, Takeda Y, et al. Significance of RRM1 and ERCC1 expression in resectable pancreatic adenocarcinoma. Oncogene. 2009;28:2903-2909. 55. Nakahira S, Nakamori S, Tsujie M, et al. Involvement of ribonucleo tide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer. Int J Cancer. 2007;120:1355-1363. 56. Valsecchi ME, Holdbrook T, Leiby BE, et al. Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma? BMC Cancer. 2012;12:104. 57. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757-1765. 58. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634.

Personalized Medicine

Oncology

June 2013

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

www.personalizedmedonc.com

PMO Interviewees include:

Michael Pellini, MD Foundation Medicine Inno52013

Edith Perez, MD Mayo Clinic

Kimberly Popovits Genomic Health

Henry T. Lynch, MD Creighton University School of Medicine

Interview With the Innovators

Personalized Medicine and Value: The Intersection of Science and Financial Viability An Interview With Experts in Healthcare Strategy John Hennessy, CMPE Sarah Cannon Nashville, Tennessee Pamela Morris Zitter Health Insights Millburn, New Jersey Randy Vogenberg, PhD, RPh Institute for Integrated Healthcare Greenville, South Carolina

he successes we have witnessed in personalized cancer therapies have caused healthcare system professionals to question whether they have traded the problem of incurable acute diseases for the responsibility of long-term maintenance therapy at unsustainable cost levels. This would present the healthcare system with a dilemma instead of a solution, since healthcare operates under the fundamental “Iron Triangle” of value: the balance of cost, quality, and access. Therefore, for personalized medicine to be regarded as progress in cancer care, it must also demonstrate value rather than just quality. And gathering, categorizing, and

understanding new and old categories of data makes the personalized medicine challenge no less than the greatest medical challenge ever to face the scientific, clinical, business, public, and policy healthcare community. To address the challenges presented to payers, Personalized Medicine in Oncology sat down with John Hennessy of Sarah Cannon, Pamela Morris of Zitter Health Insights, and Randy Vogenberg, PhD, RPh, of the Institute for Integrated Healthcare to talk about cost/value issues: drug/ diagnostic pricing, the impact of the Affordable Care Act (ACA), and the fear of bankrupting the healthcare system.

PMO We would like to thank you all for meeting with us. To start our discussion, we’d like to bring up the notion of value. Value is more than costs – it is the balance of cost, quality, and access. While personalized medicine already “pays dividends” clinically, how long will it take for it to begin paying dividends economically and become attractive to payers by showing value? Mr Hennessy Personalized medicine will translate

from something costly to something providing value as we start understanding how it can help us make better choices earlier in the treatment protocols for patients. Every patient would like to have the right care at the right time. It’s obvious that spending a couple of dollars today to get on the right path sooner equates to fewer dollars being wasted going down a wrong path that could be clinically detrimental to the patient.

Mr Hennessy is Vice President of Operations at Sarah Cannon. Ms Morris is Director, Syndicated Research at Zitter Health Insights, a research firm focusing on the impact of payers on the use of life science products. Dr Vogenberg is a founding principal of Bentelligence and a principal of its affiliate, the Institute for Integrated Healthcare.

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It takes advanced thinking and maturity in the market to get beyond the dollar I’m spending today and understanding this is a dollar I’m going to spend over a long period of time. PMO How would you articulate the value proposition justifying the costs of personalized medicine – in cancer and overall – to the clinical, business, and government sectors, as well as the patients? Mr Hennessy The value proposition for personalized medicine to the people paying the bill, whether it’s the government, your employer, or your insurer, is that we’re going to get people to the right place at the right time and give them the tools to make better decisions that are reflective of their lifestyle. The challenging aspect is making sure that we really are getting a patient to the right treatment when using personalized medicine techniques. If the only thing we’re doing is narrowing down the choices a little bit, it’s a much tougher sell. But if we can say, yes, for this particular subset of patients, I can get them to the right place very quickly and demonstrate good results, we’ll have much more success. PMO Is the pricing methodology of manufacturers for personalized medicine therapies and diagnostics becoming more sophisticated or skillful and less arbitrary so as to balance necessary profit with product affordability? Dr Vogenberg The questions around pricing for the cancer products and personalized medicine in general are becoming an increasing concern in this country through both the Medicare program and CMS as well as on the commercial insurance side of the business. The observations about pricing are a little mixed, ranging from whether they are arbitrary or if there’s some precision that’s beginning to be seen. The jury’s still out, but there is certainly opportunity to improve the methodology around pricing for these products, whether it’s for the drug, the diagnostic, or the device. Ms Morris We can speak to the payer perspective of how medications are being priced in terms of cost and efficacy. For example, if you take a therapy that’s indicated for a very broad population that might only be moderately effective for some of those folks and you weigh that

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John Hennessy, CMPE

Randy Vogenberg, PhD, RPh

against a very expensive therapy that’s indicated for a very narrow subpopulation of patients but it’s very effective in those folks, payers view those situations very differently and definitely take that into account when they are assessing per member per month cost.

There is certainly opportunity to improve the methodology around pricing for these products, whether it’s for the drug, the diagnostic, or the device. Mr Hennessy One of the questions about the affordability of these products is considering whether affordability is based on the supplier’s need for profit or whether it’s based on a value proposition for both the patient and the payer, and I think that’s left to be seen. I don’t know where that limit is or at what point it will be too expensive. But if you tell me that you had a $10,000 test that would get me to $100,000 treatment before wasting 6 months on a $50,000 treatment, that seems to make a lot of sense to me. But if it’s a $100,000 test to choose between a $5 drug and a $10 drug, I think that’s a real challenge. You’re really going to focus then

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on value of life, which is something we don’t do a good job of in this country. So hopefully the economics will be clean enough that it’s choosing between costs of treatments and not going down a more ethically challenging road, which I think is going to be really challenging for us to do as a society. PMO If a biological is developed that treats a cancer with a large patient population so well that it keeps the patients alive for the rest of their normal life expectancy, how do we avoid bankrupting the healthcare system?

How do we provide the best care to the majority of people? For payers, does that mean drawing a line in the sand in terms of quality-of-life years for a given price point? Dr Vogenberg With many of the cancer treatments today lasting for longer periods of time, particularly as it’s becoming more of a chronic disease, it raises the question of affordability for these agents as the population continues to age and we have more cancer diagnoses. As cancer care progresses and improves in precision, the question of the length of the therapy and the affordability of paying for the therapy will become increasingly important. And is it going to so-call bankrupt the system, whether it’s Medicare or the commercial insurance side, is a real issue that many are beginning to talk about and look at for solutions. In cancer care, there’s a variety of different stakeholders on the coverage side that we have to consider that are interested in affordability, whether it’s CMS on the government side or an employer, a union, or a municipality on the commercial side. All of them are facing this dilemma around affordability and avoiding its contribution to the financial pressures or potential bankruptcy. Mr Hennessy One of those things we have always looked for is that magic bullet, that 1 drug, that eradicated cancer for a patient. And that is worth something.

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It’s worth a lot. But what is that number, and how do we pay for it? I think it’s awfully hard to deal with that retrospectively. In fact, we’ve done a pretty lousy job of that when you look at the pricing of new products that come onto the market, each getting a little more expensive. There’s no reason to think that prices won’t escalate forever, particularly in an environment where we don’t have any external controls. At some point, we’re going to have to cross this bridge and ask, what’s it worth, what are we willing to pay? Interestingly, with bone marrow transplants we’ve been doing this for quite some time. There have been plenty of insurance companies that have had a maximum benefit of $100,000, $200,000, $250,000, and somehow it’s been okay. We’ve managed to work within that environment. However, in the ACA environment, where we don’t have those limitations, there are no annual limits, no out-of-pocket maximums, we run the risk of not being able to afford something. It probably would be better if we had a sense of what that affordability index was so that to the extent people are searching for this magic bullet, they also understand it’s got to be affordable at the same time. Ms Morris This is a very big question that healthcare providers, payers, and the community have been grappling with for the last several years: how do we provide the most or the best care to the majority of people? For payers, does that mean drawing a line in the sand in terms of quality-of-life years that are appropriate for a given price point? The jury is still out on that. But payers are scrutinizing price more in the context of the price/value equation. In that respect, the payer will consider the difference between an oncology product that’s approved for a very broad patient population but might only be effective in a small portion of those patients versus a product that’s approved for a very narrow subpopulation and is very effective for those individuals but might be priced really high. A payer is going to perceive these 2 situations very differently in context of cost and value of the product. In fact, payers are much less likely to heavily manage or scrutinize the cost of products if there are very few

Personalized Medicine

Oncology

June 2013

Interview With the Innovators

treatment options for that particular cancer. So unmet need plays a large factor as well. PMO Is the ACA financially compatible with the growth of personalized medicine overall and specifically in oncology, or will its additional costs reduce the spread of personalized medicine overall and in oncology in particular? Mr Hennessy I agree that the effect of the ACA in oncology is going to be really interesting. The most obvious opportunity right away is to take a portion of the population who probably didn’t have good access to oncology care and get those people into the system sooner, learn more about their disease sooner, and make changes where possible.

It’s going to introduce more people to personalized medicine, but maybe it will help us evolve personalized medicine much more rapidly than we would with a smaller population.

Payers are much less likely to scrutinize the cost of products if there are few treatment options for that particular cancer. PMO Thank you so much for taking the time to answer our questions. Your insights are very much appreciated. u

WCMC Save the date_90712_Layout 1 6/17/13 1:09 PM Page 1

2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

www.CutaneousMalignancies.com Volume 2 • No 4

www.PersonalizedMedOnc.com

June 2013

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Faculty Perspectives

JUNE 2013 • VOLUME 4 • NUMBER 1

™

RECENT ADVANCEMENTS IN THE TREATMENT OF MULTIPLE MYELOMA PUBLISHING STAFF

Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino

LETTER

FROM THE

EDITOR

Progress in the treatment of hematologic malignancies has been remarkable over the past decade, primarily due to the introduction of targeted agents, a better understanding of prognostic indicators, and new data on biomarker analysis. There is no doubt that these advances have great potential for improving outcomes; however, hematologists and oncologists who seek to provide state-of-the-art therapy for their patients may be challenged by the rapidly shifting paradigm of care. In 2013, a wealth of new data regarding the treatment of chronic lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, myelofibrosis, and multiple myeloma will be presented at major scientific meetings throughout the world. In this “Faculty Perspectives” newsletter series, we will feature highlights from several of these meetings, along with perspectives from renowned thought leaders in the field, which will provide valuable practice implications for the management of patients with hematologic malignancies. Sincerely, Paul Richardson, MD RJ Corman Professor of Medicine Harvard Medical School Clinical Director Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts

Quality Control Assistant Theresa Salerno

FACULTY

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean

Meletios A. Dimopoulos, MD Chairman, Department of Medical Therapeutics University of Athens School of Medicine Athens, Greece

Sergio A. Giralt, MD Chief, Adult Bone Marrow Transplant Service Memorial Sloan-Kettering Cancer Center Professor of Medicine Weill Cornell Medical College New York, New York

Jesús F. San Miguel, MD Professor of Hematology University of Salamanca Head of the Department of Hematology University Hospital of Salamanca Spain

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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

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

Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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Oncology

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

• Outline contemporary prognostic and predictive biomarkers and patient characteristics for multiple myeloma and apply the results to create an individualized approach to managing each patient

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

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with 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 0468-9999-13-013-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss emerging data and recent advances in the personalized treatment of patients with multiple myeloma, and integrate key findings into clinical practice

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures Karen Cooksey, Medical Writer, has nothing to disclose. She does intend to discuss either non-FDA-approved or investigational use for the following products/devices: lenalidomide, bortezomib, thalidomide, elotuzumab, MLN9708, carfilzomib, dexamethasone, cyclophosphamide, prednisone, melphalan, daratumumab, and pomalidomide. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose. Pamela Vlahakis, RN, MSN, CBCN, MLI Reviewer, has nothing to disclose. Faculty Disclosures Paul Richardson, MD, is on the Advisory Board for Bristol-Myers Squibb, Celgene Corporation, Johnson & Johnson, Millennium: the Takeda Oncology Company, and Novartis. He does not intend to discuss any non-FDA-approved or investigational use for any product/device. Meletios A. Dimopoulos, MD, is on the Advisory Board for Celgene Corporation and Ortho Biotech. He does intend to discuss either non-FDA-approved or investigational use for the following products/devices: lenalidomide and carfilzomib in the frontline treatment of MM.

Sergio A. Giralt, MD, is on the Advisory Board for and is a Consultant to Bioline, Celgene Corporation, Janssen Pharmaceuticals, Inc, Onyx Pharmaceuticals, sanofi-aventis, Seattle Genetics, Skyline Diagnostics, and Spectrum Pharmaceuticals, Inc. He does not intend to discuss any non-FDA-approved or investigational use for any product/device. Jesús F. San Miguel, MD, is on the Advisory Board for Celgene Corporation, Janssen Biotech, Millennium: the Takeda Oncology Company, Novartis, and Onyx Pharmaceuticals. He does not intend to discuss any non-FDA-approved or investigational use for any product/device. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13005A. html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1.0 hour Date of initial release: June 12, 2013 Valid for CME/CPE/CE credit through: June 12, 2014

Proceedings From a Post-IMW Roundtable Introduction The 14th International Myeloma Workshop (IMW 2013) held April 3-7, 2013, in Kyoto, Japan, was attended by renowned researchers and thought leaders from around the world. The numerous abstracts and presentations at this workshop demonstrated the outstanding progress that has been made in multiple myeloma (MM) management in the past 10 to 15 years and provided important insights for future clinical practice.

SMOLDERING MYELOMA Should Smoldering Multiple Myeloma Be Treated?

Smoldering multiple myeloma (SMM) is a precursor to symptomatic myeloma, and is characterized by an excess of monoclonal protein in the blood and urine, in which the patient experiences none of the symptoms (ie, elevated calcium levels, kidney failure, anemia, or bone lesions) typically associated with active disease.1 Overall, the risk for SMM progressing to MM is approximately 10% per year in the first 5 years.1 Although patients with SMM are at a higher risk for developing active myeloma than the general public, the current standard of care is the so-called “watch and wait” approach, in which they are regularly monitored and treatment only begins once the disease progresses to symptomatic MM. However, certain factors have been shown to be associated with an increased risk of progression in patients with SMM. These include a monoclonal protein level exceeding 30 g/L; plasma cells exceeding 10% in the bone marrow; an elevated level of phenotypically abnormal plasma cells in the bone marrow; an abnormal free light chain ratio; the presence of chromosomal abnormalities in plasma cells; and lower than normal levels of one or more types of immunoglobulin.1 At IMW 2013, María-Victoria Mateos, MD, and Jesús F. San Miguel, MD, discussed the question, “Should we treat smoldering MM?”2 They began by review-

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ing the history of studies that investigated the use of melphalan plus prednisone (MP), thalidomide, and/or bisphosphonates in patients with SMM. In the 1980s, a study by Hjorth and colleagues randomized 25 patients to receive MP therapy, started at the time of diagnosis, and another 25 patients to receive deferred therapy, in which MP was started at the time of disease progression. Results showed that no differences in response rate, duration of response (DOR), or survival were observed between treatment groups.3 Due to these findings, and the potential leukemic risk of long-term melphalan, the hematology community decided to dismiss the idea of early treatment and proposed instead that patients with SMM not be treated until they developed symptomatic disease.4 Later, when bisphosphonates were added to the MM armamentarium, investigators again decided to explore therapy for SMM. They observed that, although the number of skeletal-related events was lower and bone disease was delayed with these agents, no obvious antitumor effect was observed.5 With the advent of novel agents, the idea of early treatment was examined further.6 Witzig and colleagues conducted a small trial in which thalidomide plus zoledronic acid was compared with zoledronic acid alone for asymptomatic MM.7 Although the thalidomide arm was associated with a delay in time to biologic progression, no effect was seen regarding overall survival (OS) or time to progression (TTP) and the toxicity profile proved challenging. Therefore, the notion of treating SMM with thalidomide was not pursued.

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Figure 1. Best response rates following a median of 5.5 cycles of CRd in high-risk SMM.10

100

100%

Patients Achieving Response (%)

87.5% 80

75%

12.5%

Perspective ORR

≥VGPR

nCR/CR/sCR

VGPR

CR indicates complete response; CRd; carﬁlzomib, lenalidomide, and dexamethasone; nCR, near-complete response; ORR, overall response rate; sCR, stringent complete response; SMM, smoldering multiple myeloma; VGPR, very good partial response.

Mateos and colleagues from the Spanish Myeloma Group hypothesized that patients with standard-risk SMM may not benefit from treatment, whereas highrisk patients may desire greater benefit. Therefore, they conducted a study in 125 high-risk patients in which 1 arm received 9 cycles of treatment with lenalidomide plus dexamethasone (Rd), followed by lenalidomide maintenance therapy, whereas the control arm received no treatment until disease progression to active MM.8 The results of this study showed that high-risk patients who received early treatment had significantly better outcomes than patients who did not receive treatment until disease progression. The response rate for the experimental arm was 82%, with 26% complete response (CR). Time to disease progression was longer for the actively treated patients (not yet reached at a median follow-up of 40 months in the experimental arm vs 21 months in the control arm), as was OS at 5 years after diagnosis (94% vs 80%, respectively). Perspective “The question, ‘Should we treat SMM?’, has been raised repeatedly over the years, and previous studies indicated that there was no difference in survival between early and deferred treatment. However, none of these previous studies focused on what I think should be the target for treatment in the SMM setting: the high-risk population. When the Spanish Myeloma Group investigated the use of early treatment with Rd in high-risk SMM patients, we found a very similar response rate to what we would expect in symptomatic patients and much higher than the response rates previously reported with thalidomide. In addition, the median TTP has not been reached in the experimental arm, whereas it was 21 months in the control arm. It is also important to emphasize that tolerability of this orally administered combination therapy was very good. However, probably the most relevant finding of the study is that we have observed a significant benefit in OS with a hazard ratio (HR) of 3.4 with a 3-year OS of 94% in the experimental arm versus 80% in the control arm. I think this is showing for the first time that early treatment could be of clear benefit for patients with high-risk smoldering disease. Additional trials focusing on this SMM population are needed to confirm these results.” ~Jesús F. San Miguel, MD

Carfilzomib, Lenalidomide, and Dexamethasone in High-Risk SMM

On July 20, 2012, the US Food and Drug Administration granted accelerated approval for carfilzomib, a next-generation proteasome inhibitor, for the

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treatment of patients with MM who had received ≥2 prior therapies including bortezomib and an immunomodulatory drug, and demonstrated disease progression on or within 60 days of completion of last therapy.9 At IMW 2013, Landgren and colleagues presented preliminary outcomes for 9 evaluable patients with high-risk SMM who were treated with a combination of carfilzomib, lenalidomide, and dexamethasone (CRd) in an ongoing phase 2, single-arm, pilot study.10 Patients received eight 28-day cycles of treatment consisting of carfilzomib (20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16); lenalidomide (25 mg/day on days 1-21); and dexamethasone (20/10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23). Those who achieved stable disease or better received 12 cycles of lenalidomide maintenance therapy (10 mg/day on days 1-21). Results showed that all patients responded to CRd therapy. Responses were rapid: the median time to CR/stringent CR, which was achieved in 4 patients, was 107 days. The best response rates (after a median of 5.5 cycles) are shown in Figure 1. Grade 3/4 nonhematologic toxicities included rash/pruritus, heart failure, and liver function abnormalities. Grade 3/4 hematologic toxicities included lymphopenia, anemia, neutropenia, and thrombocytopenia.

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“In this study, there was an impressive rate of very high-quality responses to CRd, with approximately 80% of patients achieving very good partial response or better (≥VGPR). The toxicities observed included hematologic toxicities such as lymphopenia and neutropenia, as well as one case of severe heart failure that required discontinuation of therapy and another case of significant liver dysfunction. To date, none of the evaluable patients have progressed to symptomatic MM. The overall response rate (ORR) is very encouraging and warrants further study.” ~Paul Richardson, MD

NEWLY DIAGNOSED MM Cyclophosphamide, Prednisone, and Lenalidomide vs Melphalan, Prednisone, and Lenalidomide vs Lenalidomide Plus Dexamethasone

Larocca and colleagues presented the results of a multicenter phase 3 study of cyclophosphamide, prednisone, and lenalidomide (CPR) versus melphalan, prednisone, and lenalidomide (MPR) versus Rd to evaluate the best combination in 663 patients with MM who were not eligible to receive autologous stem cell transplantation (ASCT).11 Results showed that CPR, MPR, and Rd produced response rates in elderly patients (>75 years) that were similar to those seen in the overall population (Figure 2). Grade 3/4 hematologic toxicities were experienced by 62% of patients in the MPR group, 29% of those in the CPR group, and 28% of those in the Rd group. Grade 3/4 nonhematologic adverse events (AEs) were similar in the 3 groups. Perspective “I think this is an important trial because it addresses patients who are not eligible for high-dose treatment. The preliminary data indicate that Rd produces good response rates and is much better tolerated than MPR. We are eager to see the impact of this regimen on progression-free survival (PFS) and OS. In addition, it will be important to see what second malignancies are reported. I suspect that fewer secondary malignancies will develop in the group of patients receiving Rd.” ~Meletios A. Dimopoulos, MD

Carfilzomib, Cyclophosphamide, and Dexamethasone

Palumbo and colleagues presented results from a phase 2 study of carfilzomib, cyclophosphamide, and dexamethasone (CCd) in 54 patients with newly diagnosed MM.12 Patients received carfilzomib (20 mg/m2 on days 1 and 2, and 36 mg/m2 on days 8, 9, 15, and 16 in cycle 1; 36 mg/m2 on days 1, 2, 8, 9, 15, and 16 in cycles 2-9); cyclophosphamide (300 mg/m2 on days 1, 8, and 15); and dexamethasone (40 mg on days 1, 8, 15, and 22) every 28 days for 9 cycles, followed by maintenance with carfilzomib (36 mg/m2 on days 1, 2, 15, and 16) every 28 days until progression.

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Perspective “This is an important preliminary study of the frontline use of CCd. The response rate is remarkable. Essentially all patients achieved at least a PR, including approximately 1 in 4 patients who achieved an sCR. In addition, the responses were rapid. The PFS and OS data are excellent, as well. Furthermore, this treatment was well tolerated and the discontinuation rate was low; about 10% of patients discontinued treatment due to toxicities. I believe this is a very interesting combination that requires further evaluation in phase 3 trials.” ~Meletios A. Dimopoulos, MD

Cyclophosphamide, Bortezomib, and Dexamethasone

Areethamsirikul and colleagues presented results from a phase 2 study of induction therapy with the combination of cyclophosphamide (300 mg/m2 weekly); bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11); and dexamethasone (40 mg on days 1-4, 9-12, and 17-20) (CyBorD), given for four 28-day cycles, in newly diagnosed MM patients preparing for ASCT.13 Results showed an ORR of 88%, including 61% who achieved ≥VGPR. In an expanded cohort using weekly bortezomib (1.5 mg/m2) and dexamethasone (40 mg once weekly for cycles 3 and 4), similar response rates were attained (ORR 93%; ≥VGPR 60%). To compare the effectiveness of this regimen in the real-world setting, the authors reviewed their institutional experience (N=83) with CyBorD. The median age of these patients was 59 years (range, 37-71 years). MM subtypes included IgG 55%, IgA 20%, light chains only 22%, and other 3%. After a median of 4 cycles, responses were high (ORR 93%; ≥VGPR 70%). Grade 3/4 neutropenia (3.6%) and thrombocytopenia (<1%) were uncommon, and there were no cases of grade 3/4 peripheral neuropathy (PN). Dose delays/ reductions of any agents were required in 18% of patients. Stem cell mobilization was not compromised. Eighty of 83 patients proceeded to ASCT. The ORR at day +100 post-ASCT was 97% (≥VGPR 79%). The authors concluded that weekly CyBorD induction is highly effective in clinical practice, with response and toxicity profiles comparable to phase 2 trial data. Perspective “CyBorD is a highly active induction regimen for newly diagnosed patients. The therapy in this study was of particular interest because CyBorD was given weekly. I think it is very encouraging that 70% of patients had manageable toxicities with this approach and that no grade 3/4 neuropathy was reported. In fact, dose reductions were only necessary in 18% of patients and there was no compromise in stem cell collection with this regimen.” ~Paul Richardson, MD

Continuous Lenalidomide Therapy

Palumbo and colleagues reported the results of a phase 3 randomized study (MM-015), in which MPR induction followed by lenalidomide maintenance (MPR-R) was compared with MPR or MP followed by placebo in 459 transplant-ineligible patients with newly diagnosed MM who were ≥65 years of age.14 Results previously reported showed that median PFS in the overall population was significantly higher with MPR-R (31 months) than with MPR (14 months; P<.001) or MP (13 months; P<.001). The benefit was observed mainly in patients aged 65 to 75 years. At IMW 2013, the authors provided updated efficacy and safety data from this 65- to 75-year-old patient population. The proportion of patients in this

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Figure 2. Responses with CPR, MPR, and Rd: overall ITT population vs ITT population >75 years.11 100

Patients Achieving Response (%)

The median duration of treatment was 5 cycles. Responses improved with the duration of treatment reaching after 9 cycles: 100% partial response (PR), 77% VGPR, and 53% CR/near-complete response (nCR). Responses were rapid, with the median time to PR of 1 month and the median time to CR of 2 months. After a median follow-up of 7.5 months, the 1-year PFS was 87% and the 1-year OS was 88%. Grade 4 hematologic toxicities included neutropenia (5%). Grade 3/4 nonhematologic toxicities were infection (10%), cardiac events (5%), and gastrointestinal complications (2.5%). Five patients (12%) discontinued treatment and 7 patients (17%) required carfilzomib dose reductions due to AEs.

80 49%

VGPR

ITT Population >75 Years of Age

Overall ITT Population 45%

39%

54%

42%

37%

40 28% 27%

18%

13%

20%

11% 12%

Rd (n=220)

CPR (n=80)

CPR (n=222)

MPR (n=217)

14% 4%

MPR (n=86)

Rd (n=83)

CR indicates complete response; CPR, cyclophosphamide, prednisone, and lenalidomide; ITT, intent-to-treat; MPR, melphalan, prednisone, and lenalidomide; nCR, near-complete response; ORR, overall response rate; PR, partial response; Rd, lenalidomide plus prednisone; sCR, stringent complete response; VGPR, very good partial response.

age group was similar across treatment groups (76% MPR-R, 76% MPR, 75% MP). With a median follow-up of 30 months at final adjudication prior to unblinding, MPR-R significantly prolonged median PFS compared with MPR and MP (31 months vs 15 months vs 13 months, respectively; P<.001). With an updated median follow-up of 53 months, OS was 56 months with MPR-R, 54 months with MPR, and 52 months with MP. During induction, grade 3/4 neutropenia occurred in 68% (MPR-R), 63% (MPR), and 31% (MP) of patients; thrombocytopenia was reported in 36% (MPR-R), 41% (MPR), and 12% (MP); and febrile neutropenia in 4% (MPRR), 3% (MPR), and 0% (MP). During lenalidomide maintenance, the most common grade 3/4 newly occurring or worsening AEs (≥5% of patients) were thrombocytopenia (8%), anemia (7%), neutropenia (5%), diarrhea (5%), and bone pain (5%). The authors concluded that continuous treatment with lenalidomide is highly effective in transplant-ineligible patients aged 65 to 75 years, and could be considered a standard of care in this population. Perspective “This is an update of the MM-015 trial in which the subset of patients 65 to 75 years of age was analyzed. In this elderly population, no difference was seen between the 3 treatment groups in terms of OS; however, a significant improvement in PFS favoring the administration of lenalidomide maintenance was observed. This is the first trial in transplant-ineligible patients that showed an improvement in PFS with lenalidomide maintenance, and I think this information is very important. The ongoing phase 3 MM-020 study (also known as the FIRST study) is investigating Rd versus melphalan, prednisone, and thalidomide in patients with previously untreated myeloma. We expect results from that study to be presented later this year.” ~Meletios A. Dimopoulos, MD

Bortezomib Incorporated Into ASCT

At IMW 2013, Cavo and colleagues presented updated results of the outcomes of 1610 newly diagnosed MM patients, all of whom had available data on the presence or absence of del(13q), t(4;14), and/or del(17p), from the analysis of four phase 3 studies comparing up-front bortezomib (B)-based versus nonbortezomib (NB)-based single or double ASCTs.15 Results showed that, in comparison with NB-ASCTs, B-ASCTs significantly improved PFS in the overall population (HR=0.76), a benefit retained across both low-risk (HR=0.79) and high-risk (HR=0.58) subgroups, with improved OS (HR=0.85)

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CONTINUING EDUCATION seen with B-ASCTs. In a stratified multivariate analysis, independent variables associated with extended PFS and OS in the overall population included B-ASCTs (HR=0.74 and 0.79), achievement of CR (HR=0.46 and 0.44), and double ASCT (HR=0.44 and 0.31). These variables were also independent predictors for prolonged PFS and OS in patients with t(4;14) and/or del(17p). Patients who carried both of these cytogenetic abnormalities had the poorest prognosis and, in a multivariate analysis, were likely to benefit only from double ASCT (HR=0.13 for PFS and HR=0.28 for OS). The authors concluded that B-ASCTs significantly improved PFS in comparison with NB-ASCTs, but did not completely overcome the adverse prognosis related to the presence of t(4;14) and/or del(17p) and more mature data are needed before definite conclusions regarding the impact of B-ASCTs on OS can be made. Perspectives “This analysis was designed to compare outcomes for bortezomib-based induction regimens versus nonbortezomib-based induction regimens in a high-risk population that was defined by the presence of t(4;14) and/or del(17p). The results indicate that independent predictors of longer PFS and OS were bortezomib-based induction regimens, achievement of a CR, and double ASCT. The study showed a significant increase in PFS for bortezomib-treated patients in the overall population, and particularly in the population with high-risk cytogenetics. There was also a trend in favor of OS with bortezomib-based regimens. Overall, the analysis indicates that the use of bortezomib-based induction regimens improved the outcomes of patients with MM, although it did not completely overcome the detrimental effect of high-risk cytogenetics. Importantly, I think an intriguing result from this analysis was the benefit of double ASCT, particularly in patients with both abnormalities [ t(4;14) and del(17p)].” ~Jesús F. San Miguel, MD “I thought this was a very interesting presentation on many fronts. First of all, it established that the use of a proteasome inhibitor as part of induction therapy with transplant should be considered a new standard of care given the clinical benefit seen in this comprehensive analysis. In addition, this analysis provided new information about the use of double transplant in patients with high-risk cytogenetics. Prior to the era of novel therapies, the use of transplant in this high-risk group wasn't just ineffective, it was actually deleterious, presumably enhancing resistance, particularly in the del(17p) patients. Therefore, these results potentially provide a biological clue that the rebooting of the immunological profile of the patient with ASCT in conjunction with novel therapies may create a new therapeutic paradigm.” ~Paul Richardson, MD

Bortezomib, Reduced-Intensity ASCT, Followed by Lenalidomide

Magarotto and colleagues reported the results of a multicenter phase 2 study that evaluated a sequential approach including ASCT in 102 elderly patients with newly diagnosed MM.16 Patients received 4 cycles of bortezomib, pegylated doxorubicin, and dexamethasone, followed by tandem melphalan (100 mg/ m2) and ASCT (MEL100-ASCT), 4 cycles of lenalidomide plus prednisone (LP) consolidation, and lenalidomide maintenance until progression. In an intent-to-treat analysis, the CR rate was 33% after MEL100-ASCT, 49% after LP, and 54% after lenalidomide maintenance. At a median follow-up of 66 months, median TTP was 55 months, median PFS was 48 months, median OS was not reached, and OS at 5 years was 63%. The achievement of CR correlated with longer TTP (median, 70 months), PFS (median, 63 months), and OS (83% at 5 years). Median survival from relapse was 28 months. Overall, the main grade 3/4 toxicities included thrombocytopenia, neutropenia, infections, PN, gastrointestinal AEs, dermatologic toxicity, and thromboembolism. The incidence of second malignancies (skin cancer excluded) was 0.5% per year of follow-up. Deaths related to AEs occurred in 8 of 102 patients (only during induction or transplantation) and were higher in patients >70 years than in younger patients (19% vs 5%; P=.024). Perspective “I would like to highlight several points in this interesting trial conducted in

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early myeloma patients. First, the CR rate is very high; it started at 33% and at the end of the study was 54%. In the maintenance phase, there was a prolonged PFS of 48 months and an OS at 5 years of 63%. I think this speaks in favor of aggressive treatment in this cohort of patients. Nevertheless, I believe that the major issue was the treatment-related mortality in patients older than 70 years. Therefore, from my point of view, this intensive approach may be a valid alternative for fit patients without comorbidities who are younger than 70 years.” ~Jesús F. San Miguel, MD

Early vs Delayed Transplantation

At IMW 2013, Philippe Moreau, MD, and Paul Richardson, MD, discussed the question, Should ASCT be used early in all eligible patients, or kept in reserve as a salvage treatment at the time of progression for selected patients achieving a high-quality response?17 In 2009, Stewart and colleagues published an article in which they wrote, “A reasonable goal of MM treatment in younger ‘transplant eligible’ patients is to initiate therapy with a target goal of durable complete remission, and the anticipated consequence of long-term disease control. To achieve this goal we recommend induction therapy with multiagent combination chemotherapies (usually selected from bortezomib, lenalidomide, thalidomide, cyclophosphamide, and corticosteroids) which when employed together elicit frequent, rapid, and deep responses. We recommend consolidation with high-dose melphalan and ASCT in the majority of patients willing and able to undergo this procedure and subsequent maintenance therapy in those failing to achieve a CR or at high risk for early relapse based on prognostic, genetically defined risk factors. Defining genetic risk for early relapse is therefore an important aspect of early diagnostic testing, and attention to minimizing expected toxicities once therapy begins is critical in ensuring the efficacy of modern combination therapy approaches.”18 In 2010, Cavo and colleagues conducted a randomized phase 3 study of bortezomib, thalidomide, and dexamethasone (VTD) compared with thalidomide plus dexamethasone (TD) as induction therapy before, and consolidation therapy after, double ASCT in 480 newly diagnosed MM patients.19 After induction therapy, CR or nCR was achieved in 31% of patients who received VTD, and 11% of patients who received TD (P<.0001). The authors concluded that VTD induction therapy before double ASCT significantly improves rate of CR or nCR, and represents a new standard of care for patients with MM who are eligible for transplant. Richardson and colleagues at the Dana-Farber Cancer Institute conducted a phase 1/2 study of lenalidomide, bortezomib, and dexamethasone (RVD) combination therapy in 66 patients with newly diagnosed MM.20 One hundred percent of patients achieved ≥PR, with 74% in the phase 2 study and 67% of patients overall achieving ≥VGPR. Twenty-eight patients (42%) proceeded to transplantation. With a median follow-up of 21 months, estimated 18-month PFS and OS for RVD with and without transplantation were 75% and 97%, respectively. In 2011, Moreau and colleagues from the Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib plus dexamethasone (VD) as induction before high-dose therapy and ASCT versus a combination of reduced doses of VTD in 199 newly diagnosed MM patients.21 After 4 cycles, the CR rate was the same in both groups (13% in the VTD arm, 12% in the VD arm; P=.74). However, the CR plus VGPR rate was significantly higher in the VTD arm (49% vs 36%; P=.05). After ASCT, the CR plus VGPR rate was 74% in the VTD arm versus 58% in the VD arm (P=.02). McCarthy and colleagues conducted a study to determine whether lenalidomide maintenance therapy prolongs TTP after ASCT in 460 patients who were younger than 71 years and who had SD or a minimal response (MR), PR, or CR 100 days after undergoing ASCT.22 The study-drug assignments were unblinded when a planned interim analysis showed a significantly longer TTP in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease (PD) or had died (P<.001). Of the remaining 128 patients who received placebo and who did not have PD, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients (37%) who received lenalidomide and 132 of 229 patients (58%) who received placebo had disease progression or had died. The median TTP was 46 months in the lenalidomide group and

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FACULTY PERSPECTIVES 27 months in the placebo group (P<.001). More grade 3/4 hematologic and grade 3 nonhematologic AEs occurred in patients who received lenalidomide (P<.001 for both comparisons). Second primary malignancies (SPMs) occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%). The authors concluded that lenalidomide maintenance therapy, initiated at day 100 after ASCT, was associated with greater toxicity and secondary cancers but a significantly longer TTP and significantly improved OS. Attal and colleagues also conducted a phase 3, placebo-controlled trial investigating the efficacy of lenalidomide maintenance therapy in 614 patients <65 years of age who had nonprogressive disease after first-line ASCT.23 Results showed that the median PFS was 41 months with lenalidomide maintenance therapy versus 23 months with placebo (P<.001). The incidence of SPMs was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patientyears in the placebo group (P=.002). Median event-free survival (EFS) (with events that included SPMs) was significantly improved with lenalidomide (40 months vs 23 months with placebo; P<.001). The authors concluded that lenalidomide maintenance after transplantation significantly prolonged PFS and EFS. Four years after randomization, OS was similar in the 2 study groups but more mature follow-up on these outcomes is eagerly awaited. Perspectives “In the comparison of early versus delayed transplant, the data that are available so far are in favor partially of early transplant based on the Siegel study derived from the ECOG trial in which lenalidomide plus high-dose or low-dose dexamethasone were analyzed. One subset of patients continued on primary therapy while another subset received early transplant. The 3-year OS was in favor of the patients who received early transplant.24 We also have data from a randomized trial in which, after 4 cycles of Rd, the patients were randomized to receive either 6 cycles of MPR or MEL-200 and then maintenance or no maintenance.25 So far, the study indicates that high-dose melphalan and autologous transplant is associated with a significant benefit in 2-year PFS, but no difference in OS. My personal position regarding early versus delayed ASCT is in favor of early transplant until we see results from the ongoing randomized IFM/ DFCI2009 trial,26 which is comparing conventional dose treatment using RVD versus high-dose treatment with peripheral ASCT in the initial management of myeloma in patients 65 years or younger. Until this data is available, I prefer early transplant because the patient is more fit upfront to tolerate intensive and repetitive therapies and is also more prepared psychologically for intensive therapies. In addition, I favor early transplant because it is associated with long-term treatment-free intervals during which patients experience an excellent quality of life, and also because, in countries such as Spain, transplant is a less costly approach than those that use novel agents. My final argument for offering my patients early transplant (until the randomized data from the aforementioned trial becomes available) is that, at the time of relapse after MEL-200, patients are very sensitive to novel agents. I don't know yet what the efficacy of MEL-200 is after long-term exposure to novel agents. This is because most of the data that we have so far with late transplant has been with chemotherapy, not novel agents. Therefore, for these reasons I prefer to be conservative and continue to offer early autologous transplant until data from randomized trials become available.” ~Jesús F. San Miguel, MD “The current data that we have in support of early transplant are based on regimens that do not include a proteasome inhibitor. Because of this, it is still premature to say that early transplant is the standard. I think we recognize that, for a proportion of patients, early transplant may be beneficial. The key question is: Is it beneficial for all patients? In the United States, patients remain quite reluctant to undergo early transplant—particularly with the excellent results now achieved with novel therapy combinations. I think Dr San Miguel’s point about resistance is well taken but, certainly from a pharmacological standpoint, one might expect the opposite, where resistance after prior conventional chemotherapy with melphalan would be the worry but would not be so with novel therapies. In fact, we didn't see this in our current studies, suggesting that we wouldn't expect primary resistance. However, I do agree that the timing of myeloablation and immunological

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reconstitution is a critical question, and I think this is what we'll learn from the ongoing randomized trials. The notion that patients are better able to tolerate a transplant early does certainly apply to a subgroup of patients, but not to all patients. Regarding psychological readiness for transplant, some patients actually find undergoing transplant later in their disease course somewhat easier to come to terms with than they would have soon after diagnosis. In addition, we must be concerned about genotoxic injury in a small subset of patients who are vulnerable to secondary myelodysplasia and leukemia. Therefore, it is very important to identify these patients and potentially spare them from the real risk of such complications both acutely and long term.” ~Paul Richardson, MD

RELAPSED/REFRACTORY MM Lenalidomide Plus Low-Dose Dexamethasone

At IMW 2013, Gomes presented results of a retrospective study in 7 first-relapse MM patients with severe renal impairment (creatinine clearance [CrCl] <30 mL/min) who were treated with Rd.27 Results showed an ORR of 71% (5/7 patients). The 2 patients who did not respond had prior exposure to thalidomide. The median DOR was 21 months, and in 4 of 7 patients (57%) the response was longer than 2 years. Forty-three percent of patients experienced renal improvement, and 2 patients continued on dialysis. No serious infections or SPMs were observed.

Perspective “As we are all aware, the first relapse after initial primary therapy is extremely difficult to treat and we have very little randomized phase 3 data on this population. In addition, while it is difficult to treat patients in this population who have normal renal function, it is even more difficult to treat those patients with impaired renal function. This is especially true because there is a false perception that lenalidomide should not be used in patients with impaired renal function even though adequate guidelines have been published on how to safely use this drug in patients with low CrCl. The study by Gomes demonstrated that good, durable remissions with an acceptable safety profile could be achieved when Rd was administered to a group of first-relapse patients with severe renal impairment. Although the number of patients was relatively small, these preliminary results suggest that this combination may be helpful for such patients who cannot take bortezomib or for whom carfilzomib is not available.” ~Sergio A. Giralt, MD

Pomalidomide Plus High- vs Low-Dose Dexamethasone

Dimopoulos and colleagues reported updated survival results of a phase 3, multicenter, randomized, open-label study (MM-003) of pomalidomide plus either low-dose dexamethasone (POM+LoDEX) or high-dose dexamethasone (POM+HiDEX) in 455 patients with relapsed/refractory MM.28 Patients must have been refractory to their last prior therapy (ie, they must have developed PD during or within 60 days) and failed lenalidomide and bortezomib (alone or in combination) after receiving ≥2 consecutive cycles of each. The study design was described previously at ASH 2012.29 Patients had received a median of 5 prior therapies and 72% were refractory to lenalidomide and bortezomib. Median follow-up was 4 months. PFS and OS were significantly longer in the group that received POM+LoDEX than the group that received POM+HiDEX in the overall population, as well as in patients refractory to lenalidomide and bortezomib, in those with lenalidomide or bortezomib as their last prior therapy, and in both those with normal (CrCl ≥60 mL/min) or moderately impaired (CrCl <60 mL/min) renal function. After data evaluation, the Data Monitoring Committee recommended crossover from POM+HiDEX to POM+LoDEX. With updated data, ORRs were 21% for POM+LoDEX and 3% for POM+HiDEX (P<.001). The most frequent grade 3/4 AEs for the lowdose versus high-dose dexamethasone groups were neutropenia (42% vs 15%), anemia (27% vs 29%), and infections (24% vs 23%). The rates of discontinuations due to AEs were low: 7% in the POM+LoDEX group and 6% in the POM+HiDEX group.

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Figure 3. Responses to POM+LoDEX vs pomalidomide alone.30

Table. Determining the MTD in a Phase 1 Study of PVD31

ORR

Patients Achieving Response (%)

PR CR

40 34% 31%

Number of Patients

Bortezomib Dose (Days 1, 4, 8, 11a)

Low-Dose Dexamethasone Dose (Days 1-2, 4-5, 8-9, and 11-12b)

1 mg/day

1 mg/m2

20 mgc

2 mg/day

1 mg/m2

20 mgc

3 mg/day

1 mg/m2

20 mgc

4 mg/day

1 mg/m2

20 mgc

4 mg/day

1.3 mg/m2

20 mgc

Cohort 6 (Expansion Cohort; n=6) at MTD/MPD

For cycles 1-8, then Days 1 and 8 for cycle 9 and beyond. For cycles 1-8, then Days 1-2 and 8-9, for cycles 9 and beyond. 10 mg for patients older than 75 years.

15%

14%

MTD indicates maximum planned dose; MTD, maximum tolerated dose; PVD, pomalidomide, bortezomib, and low-dose dexamethasone.

3% 0

Pomalidomide + Low-Dose Dexamethasone (n=113)

1% Pomalidomide Alone (n=108)

CR indicates complete response; ORR, overall response rate; PR, partial response.

Perspective “I think this randomized, controlled phase 3 trial is very important because it evaluates the role of a novel combination, pomalidomide plus low-dose dexamethasone, in patients with very advanced, refractory myeloma. The control arm received high-dose dexamethasone because patients for whom lenalidomide and bortezomib are not options, and who have no access to clinical trials with novel investigational agents, steroids (such as high-dose dexamethasone) are frequently administered to palliate their disease. The main finding of the study is that the administration of pomalidomide with low-dose dexamethasone improves PFS. In fact, the PFS is doubled with this regimen. In addition, an OS advantage clearly favoring this combination was seen. This regimen was relatively well tolerated, considering the advanced nature of the disease in this population of patients, who have frequent infectious episodes and borderline blood counts. The main toxicity observed was myelosuppression. The main nonhematologic toxicities were infections, which were equally distributed between the 2 groups. It is important to note that no significant deep-vein thrombosis or PN were reported with this regimen.” ~Meletios A. Dimopoulos, MD

Pomalidomide Plus Low-Dose Dexamethasone

Jagannath and colleagues presented the results of a multicenter, randomized, open-label phase 2 study (MM-002) evaluating the safety and efficacy of pomalidomide alone versus POM+LoDEX in 221 patients with relapsed and refractory MM who have received multiple prior therapies, including lenalidomide and bortezomib.30 The encouraging responses for the overall population are shown in Figure 3. The median DOR (for patients who achieved ≥PR) was 45 months in the POM+LoDEX group and 31 months in the pomalidomide alone 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 PFS for the overall population was 4.6 months for those who received POM+LoDEX and 2.6 months for those who received pomalidomide alone. The most common grade 3/4 AEs were neutropenia (41%), anemia (22%), thrombocytopenia (19%), and pneumonia (22%). Tolerability was similar across the different age groups. The authors concluded that, in patients with relapsed and refractory MM who have received multiple prior treatments including lenalidomide and bortezomib, pomalidomide (with or without low-dose dexamethasone) was clinically effective and generally well tolerated. Response rates were encouraging and consistent, as well as durable regardless of age.

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Perspective “In our intent-to-treat analysis, we found that efficacy outcomes for the overall population of the subgroups were very promising in such a heavily treated population. In the patients who were younger than 65 years, the ≥PR rate for POM+LoDEX was 31%, and the ≥MR rate was 47%. These rates were similar in the older patients (37% and 43%, respectively). The median DOR rates were also similar between groups. The results of this analysis show that patients with relapsed and refractory MM respond well to POM+LoDEX, irrespective of age.” ~Paul Richardson, MD

Pomalidomide, Bortezomib, and Low-Dose Dexamethasone

Richardson and colleagues presented results of a phase 1 multicenter, dose-escalation study (MM-005) of pomalidomide, bortezomib, and low-dose dexamethasone in 15 patients with relapsed and/or refractory MM.31 Patients were divided into 5 cohorts in a 3 + 3 design for 21-day cycles, as shown in the Table, followed by an expansion cohort. They were evaluated every 21 days and followed for 5 years. Patients with 1 to 4 prior antimyeloma therapies, PD during a lenalidomide-containing treatment or within 60 days of last dose, and proteasome inhibitor exposure (but not bortezomib-refractory) were eligible to participate. All 15 patients had prior lenalidomide and bortezomib exposure; 73% of patients had progressed on lenalidomide as their last prior regimen. As of October 15, 2012, no dose-limiting toxicities (DLTs) were observed. Confirmation of the maximum tolerated dose is ongoing. Grade 3/4 AEs included thrombocytopenia (27%) and neutropenia (27%). Grade1/2 PN (none painful) occurred in 4 patients. No thromboembolism occurred. Three patients discontinued therapy, but none due to AEs. At the data cutoff, 73% of patients had achieved ≥PR, including 27% VGPRs (Figure 4). Responses were also observed in patients with adverse cytogenetic profiles. Perspective “In this trial, patients had to have received 1 to 4 prior anti-myeloma therapies; it was required that they were refractory to lenalidomide but had to be responsive to bortezomib. The ORR was 73% at data cutoff, with a rapid median time to response and very favorable tolerability. This regimen will now provide a platform for an ongoing phase 3 trial of pomalidomide 4 mg, bortezomib 1.3 mg/m2, and dexamethasone 20 mg (according to the schedule described) versus bortezomib, dexamethasone, and placebo administered on the classic schedule (D 1, 4, 8, 11 every 21 days).” ~Paul Richardson, MD

MLN9708

At IMW 2013, Kumar and colleagues reported the safety and pharmacokinetic results of early studies of MLN9708, administered alone in relapsed/ refractory MM patients or in combination with lenalidomide and dexameth-

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FACULTY PERSPECTIVES

Figure 4. Duration of responses with PVD.31

Unconﬁrmed PR as of data cut. PD indicates progressive disease; PR, partial response; PVD, pomalidomide, bortezomib, and lowdose dexamethasone; SD, stable disease; VGPR, very good partial response.

asone in newly diagnosed MM patients.32-34 In the ongoing phase 1 single-agent study in relapsed/refractory MM patients, DLTs included grade 3 rash and gastrointestinal AEs. Common drug-related AEs included thrombocytopenia (45%), diarrhea (37%), and nausea (35%); grade ≥3 AEs included thrombocytopenia (33%), diarrhea (17%), and neutropenia (17%). Grade 1/2 PN was observed in 10% of patients, with no grade ≥3 PN observed. Pharmacokinetic data showed rapid absorption, a terminal half-life of 4 to 12 days, and a proportional increase in plasma area under the curve with dose (0.8-3.95 mg/m2). Thus, single-agent MLN9708 appeared generally well tolerated; the long terminal half-life supports weekly dosing.33 In an ongoing phase 1/2 study of MLN9708 plus lenalidomide and dexamethasone in newly diagnosed patients, common AEs included rash (68%), fatigue (48%), nausea (42%), and PN (32%; 3% grade 3). MLN9708 pharmacokinetic data showed no apparent differences between single-agent and combination dosing, suggesting no pharmacokinetic interaction with lenalidomide or dexamethasone.34 Data from these studies provide the rationale for weekly dosing of MLN9708 at 4.0 mg combined with lenalidomide and dexamethasone in an ongoing phase 3 trial in relapsed/refractory MM. MLN9708 in combination with lenalidomide and dexamethasone is also being evaluated in another phase 3 study in patients with newly diagnosed MM who are not candidates for transplant. Perspective “MLN9708 has been referred to as ‘the oral bortezomib.’ We were all impressed regarding the response rates in patients with relapsed/refractory myeloma as well as in the upfront setting. I think we are going to see a new generation of anti-myeloma agents that have new mechanisms of action (eg, monoclonal antibodies) and oral agents that will make treatment much easier to administer.” ~Sergio A. Giralt, MD

References

1. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302:1347–1349. 2. Mateos MV, San Miguel J. Should we treat smoldering multiple myeloma? Haematologica. 2013;13(suppl 1):S20-S21. Abstract S11-3. 3. Hjorth M, Hellquist L, Holmberg E, et al. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993;50:95-102. 4. San Miguel JF, Bladé Creixenti J, García-Sanz R. Treatment of multiple myeloma. Haematologica. 1999;84:36-58. 5. Musto P, Petrucci MT, Bringhen S, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer. 2008;113: 1588-1595. 6. Barlogie B, van Rhee F, Shaughnessy JD Jr, et al. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008;112:3122-3125.

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7. Witzig TE, Laumann KM, Lacy MQ, et al. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013;27:220-225. 8. Mateos MV, López-Corral L, Hernández M, et al. Smoldering multiple myeloma (SMM) at high-risk of progression to symptomatic disease: a phase III, randomized, multicenter trial based on lenalidomide-dexamethasone (Len-Dex) as induction therapy followed by maintenance therapy with Len alone vs no treatment. Blood (ASH Annual Meeting Abstracts). 2011;118. Abstract 991. 9. Krypolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012. 10. Landgren CO, Manasanch E, Kwok M, et al. Phase II study: carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (Dex) in high risk SMM (early myeloma). Haematologica. 2013;13(suppl 1):S39-S40. Abstract O-6. 11. Larocca A, Magarotto V, Offidani M, et al. Lenalidomide-dexamethasone vs melphalan-prednisone-lenalidomide vs cyclophosphamide-prednisone-lenalidomide in NDMM. Haematologica. 2013;13(suppl 1):S113-S114. Poster P-146. 12. Palumbo A, Bringhen S, Petrucci MT, et al. A phase II trial of carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma patients. Haematologica. 2013;13(suppl 1):S112-S113. Abstract P-145. 13. Areethamsirikul N, Masih-Khan E, Chu CM, et al. CyBorD induction therapy for multiple myeloma in clinical practice. Haematologica. 2013;13(suppl 1):S140. Abstract P-202. 14. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide therapy in patients with newly diagnosed MM aged 65-75 years: MM-015 update. Haematologica. 2013;13(suppl 1):S152. Abstract P-227. 15. Cavo M, Sonneveld P, Moreau P, et al. Impact of bortezomib incorporated into auto transplantation on outcomes of myeloma patients with high-risk cytogenetics. Haematologica. 2013;13(suppl 1):S158-S-159. Abstract P-241. 16. Magarotto V, Gay F, Rossi G, et al. Bortezomib, reduced-intensity transplantation followed by lenalidomide for newly diagnosed elderly MM patients. Haematologica. 2013;13(suppl 1): S119-S120. Abstract P-158. 17. Moreau P, Richardson P. Debate: early or delayed transplantation for multiple myeloma in the era of novel therapies: does one size fit all? Haematologica. 2013;13(suppl 1):S17. Abstract S9-4. 18. Stewart AK, Richardson PG, San-Miguel JF. How I treat multiple myeloma in younger patients. Blood. 2009;114:5436-5443. 19. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 20. 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. 21. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduceddose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118: 5752-5758; 5982. 22. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781. 23. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 24. Siegel DS, Jacobus S, Rajkumar SV, et al; on behalf of the Eastern Cooperative Oncology Group. Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in the ECOG E4A03 randomized clinical trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 38. 25. Palumbo A, Cavallo F, Hardan I, et al. A phase III study to compare melphalan, prednisone, lenalidomide (MPR) versus melphalan 200 mg/m2 and autologous transplantation (MEL200) in newly diagnosed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 3573. 26. ClinicalTrials.gov. Study Comparing Conventional Dose Combination RVD to High-Dose Treatment With ASCT in the Initial Myeloma up to 65 Years (IFM/DFCI2009). http://clinicaltrials.gov/ct2/show/NCT01191060. 27. Gomes FR. Lenalidomide in the treatment of first relapsed multiple myeloma patients with severe renal impairment. Haematologica. 2013;13(suppl 1):S95. Abstract P-108. 28. Dimopoulos MA, Weisel KC, Moreau P, et al. Progression-free survival (PFS) and overall survival (OS) advantages with pomalidomide + low-dose dexamethasone: MM-003. Haematologica. 2013;13(suppl 1):S134. Abstract P-189. 29. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with low-dose dexamethasone demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory MM: a phase 3, multicenter, randomized, open-label study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract LBA-6. 30. 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. 31. Richardson PG, Hofmeister CC, Siegel DS, et al. Ph 1 trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma. Haematologica. 2013;13(suppl 1):S128-S129. Poster P-178. 32. Kumar S, Niesvizky R, Berdeja JG, et al. Safety and pharmacokinetics of weekly MLN9708, an investigational oral proteasome inhibitor, alone and in combination. Haematologica. 2013;13(suppl 1):S154. Abstract P-230. 33. Kumar S, Bensinger WI, Craig B, 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. 34. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 332.

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Gene Profiling in Colon Cancer: How to Integrate Profiling Into Practice Katherine Van Loon, MD, MPH Chloe E. Atreya, MD, PhD R. Kate Kelley, MD Alan P. Venook, MD Helen Diller Family Comprehensive Cancer Center University of California, San Francisco, California

Key Points • In a climate of increasing molecular testing capabilities, clinicians are urged to approach the commercially available biomarker tests with a healthy level of scrutiny toward clinical validation • The utility of predictive biomarkers must be linked to companion drugs • Early data from clinical applications of molecular assays suggest that a pairing of mutational analyses with investigational therapeutics may be a practice paradigm for the near future

he premise behind the “individualization of cancer care” assumes that there are subsets of patients with tumors harboring clinically relevant targets for patient-specific treatments. Currently, very little of the genomic information in colon cancer has clear clinical applicability; however, recent developments raise the prospects for better matching of patients with treatments. This optimism derives from the sentinel discovery of a strong and discrete predictive biomarker in colon cancer: the association of KRAS mutations with the lack of efficacy of epidermal growth factor receptor (EGFR) antibodies. The importance of KRAS became apparent in 2008 when the first evidence was presented that codon 12 and codon 13 KRAS mutations were pre-

dictive of resistance to EGFR monoclonal antibodies in patients with metastatic colon cancer.1 As one would predict, the utilization of EGFR inhibitors subsequently declined as oncologists tailored therapeutic plans to limit exposure to inactive agents for this subset of colon cancer patients.2 It is possible that this knowledge has even resulted in inappropriate underuse of these agents.2 Beyond KRAS, however, the search for predictive biomarkers for colon cancer has been largely unproductive, leaving the promise of personalized care for this disease generally unfulfilled. Clinical decision making in colon cancer stands in stark contrast to the management of breast cancer, where the status of such markers as the estrogen receptor, progesterone receptor, HER2-neu, and a 21-gene

Dr Van Loon is Assistant Clinical Professor, University of California, San Francisco (UCSF). She is a gastrointestinal cancer specialist, with a particular interest in colon cancer. Dr Atreya is Adjunct Instructor at UCSF. She is a gastrointestinal oncologist and scientist whose research focuses on the interplay between genotype and response to therapy in advanced colorectal cancer. Dr Kelley is Assistant Professor at UCSF. She is a gastrointestinal oncologist with a research interest in developing biomarkerstratified clinical trials to identify new treatments, particularly for hepatocellular and bile duct cancers. Dr Venook is Professor at UCSF. He is a nationally renowned expert in colorectal and liver cancers at the UCSF Helen Diller Family Comprehensive Cancer Center, where he leads the gastrointestinal oncology program.

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recurrence score impact treatment planning. Similarly, the field has been outpaced by biomarker discoveries in nonâ&#x20AC;&#x201C;small cell lung cancers, where crizotinib has been validated for treatment of ALK-rearranged tumors and EGFR inhibitors are validated for use in tumors that harbor EGFR mutations.3,4 Meanwhile, for a disease that is actually notable for its dearth of predictive biomarkers, commercially available molecular diagnostic assays are numerous and applied to colon cancer patients with surprising frequency. As clinicians, we are routinely engaged in complex discussions with patients regarding the role for or interpretation of these tests. Here, we review the biomarker discoveries in colon cancer and discuss the appropriate integration of relevant molecular diagnostic assays into clinical practice.

KRAS KRAS mutations in codons 12 and 13 of exon 2 are present in approximately 40% of colon cancers.5,6 When first analyzed, an enlarging body of literature concluded that KRAS codon 12 and 13 mutations are predictive of lack of response to monoclonal antibodies directed against EGFR that inhibit its downstream signaling pathways (cetuximab and panitumumab).1,5,7-13 Current National Comprehensive Cancer Network Guidelines recommend universal testing for KRAS mutations in codons 12 and 13 of exon 2 in patients with metastatic colon cancer,14 and FDA labels for both cetuximab and panitumumab recommend against their use in patients whose tumors harbor KRAS mutations. More recent reports, however, have challenged this undiscriminating approach with data suggesting that KRAS codon 12 and 13 mutations may be distinct, despite coding for adjacent amino acids.15,16 In patients treated with cetuximab, the change of a glycine (G) to aspartic acid (D) at codon 13 of KRAS (c.38G>A, or p.G13D) was associated with survival that was intermediate between that of patients with KRAS wildtype tumors and tumors with a KRAS mutation at glycine-12. The finding that G13D mutations may be associ-

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Katherine Van Loon, MD, MPH

Alan P. Venook, MD

ated with intermediate outcomes confounds our understanding of how KRAS mutations impact colon cancer prognosis.15,16 This should be considered hypothesis generating only; the clinical question of whether a patient with metastatic colon cancer harboring a KRAS G13D mutation will benefit from, be harmed, or be unaffected by anti-EGFR therapy remains unanswered. Accounting for the modest benefit of anti-EGFR therapy even among patients with KRAS wild-type tumors, the sample size necessary to prospectively answer this question is prohibitive. Currently, anti-EGFR agents

The response rate to anti-EGFR monotherapy is approximately 15% among patients with KRAS codon 12 and 13 wild-type metastatic colorectal cancer. are not recommended in routine practice for treatment of patients whose tumors have a G13D mutation and should only be used in the context of an investigational trial.14 The response rate to anti-EGFR monotherapy is approximately 15% among patients with KRAS codon 12 and 13 wild-type metastatic colorectal cancer.5 A number of retrospective and basic research studies have

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aimed to identify additional markers that may enrich for response. Rare KRAS mutations at codons 61 and 146 and activating mutations in other genes downstream of EGFR (eg, NRAS, BRAF, and PIK3CA) may predict decreased likelihood of benefit from cetuximab or pan itumumab.17-20 At this time, however, there is insufficient evidence to restrict anti-EGFR therapy to patients with so-called “quadruple-negative” tumors (wild-type for KRAS, NRAS, BRAF, and PIK3CA).18,19 Similarly, the association between HER2 amplification or loss of PTEN expression with resistance to EGFR-targeted agents remains investigational.18,20

BRAF BRAF mutations are present in approximately 10% of colon cancers and are almost exclusively found in patients with wild-type KRAS. BRAF is a serine/threonine kinase immediately downstream of KRAS in the mitogen-activated protein kinase (MAPK) signaling pathway. BRAF-mutant colon cancers typically harbor a valine (V) to glutamic acid (E) change at codon 600

The CAIRO2 and COIN trials found that the poor prognosis associated with BRAF mutation was unchanged by cetuximabcontaining first-line regimens. (c.1799T>A or p.V600E). BRAF mutations strongly associate with hypermutated tumors, frequently exhibiting a CpG island methylator phenotype and sporadic microsatellite instability (MSI).21-23 Similar to larger population-based studies, The Cancer Genome Atlas Network observed BRAF mutations in 3% of nonhypermutated and 47% of hypermutated colon cancers (n=165 and n=30, respectively).24 BRAF V600E is an adverse prognostic marker in metastatic colon cancer, independent of therapy.6,25-27 The presence of a BRAF mutation may diminish the more favorable prognosis afforded by MSI; the intersection of BRAF and MSI status is an area of ongoing

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investigation.6,27,28 Whereas KRAS codon 12 mutations clearly predict lack of benefit from EGFR-targeted antibodies, the predictive import of BRAF V600E is less certain. In a pooled analysis of the CRYSTAL and OPUS randomized clinical trials, the addition of cetuximab to first-line chemotherapy showed a nonsignificant trend toward improved progression-free survival (PFS) and overall survival (OS) for BRAF-mutant metastatic colon cancers.5 The CAIRO2 and COIN trials found that the poor prognosis associated with BRAF mutation was unchanged by cetuximab-containing first-line regimens.26,29 In the chemotherapy-refractory setting, patients with aggressive BRAF-mutant colon cancers are uncommon but appear unlikely to benefit from cetuximab.15,30 Personalized treatment is needed for patients with BRAF-mutated metastatic colon cancer. Vemurafenib transformed treatment of BRAF-mutated metastatic melanoma, but unfortuntately, single-agent efficacy of the BRAF inhibitor was minimal in colon cancer.31 Outcomes of combined inhibition of BRAF and MEK are more promising.32,33 As reported at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, among 34 patients with BRAF V600 mutant metastatic colon cancer treated with dabrafenib plus trametinib, 1 patient (3%) achieved a complete response and 3 patients (9%) achieved a partial response; 7 of 18 patients with disease stabilization achieved a minor response.32 Compared with melanoma, colon cancers have high EGFR expression and ligand production. Several preclinical studies suggest that signaling through EGFR is a key mechanism of resistance to BRAF inhibitors in colon cancer.34,35 Two multicenter phase 1/2 clinical trials combining a BRAF inhibitor with an EGFR-targeted antibody (NCT01750918 and NCT01719380) are now recruiting. We recommend consideration of screening all patients with KRAS wild-type metastatic colon cancer for a BRAF mutation based on its well-established negative prognostic value in this clinical context. Those positive for a mutation should be evaluated for clinical trial candidacy in light of their significantly poorer outcomes with standard therapy.

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Multigene Recurrence Scores There are currently several commercially available multigene assays that aim to inform decisions regarding the role for adjuvant chemotherapy in patients with stage II and III colon cancer. The first of these to be commercialized was the Oncotype DX Colon Cancer Assay (Genomic Health, Inc), which became available in January 2010.36 This assay quantifies expression of 7 recurrence-risk genes and 5 reference genes expressed in fixed, paraffin-embedded tumor specimens using reverse transcriptase-polymerase chain reaction to generate a score that corresponds to a low, intermediate, or high risk of recurrence.37 The clinical applicability of the recurrence score is strengthened by the identity of the genes and the fact that 6 of 7 genes reside in key pathways for cell cycle control (MKI67, MYC, MYBL2) and stromal response (FAP, BGN, INHBA).37 The seventh gene (GADD45B) is a marker of genotoxic stress and is thought to possibly regulate stromal response genes, including BGN.38 A retrospective validation of the Oncotype DX Colon Cancer Assay was performed using 1436 tissue blocks from patients in the randomized QUASAR study that compared adjuvant 5-fluorouracil with observation in patients with stage II disease; a continuum of low, intermediate, and high scores corresponded to estimated recurrence risk at 3 years of 12%, 18%, and 22%, respectively. According to these data, the Oncotype DX recurrence assay appears to discriminate the absolute increase in recurrence risk at 3 years by 10% along the continuum from low- to high-risk patients. Because the recurrence risk reduction from chemotherapy was proportional across all risk groups in the QUASAR data set, the assay has not been validated as a predictor of benefit from chemotherapy, although the benefit is marginally greater as the risk increases. A second validation study was performed on tumor specimens from 690 patients enrolled in CALGB 9581, which found no effect of adjuvant edrecolomab compared with observation in patients with resected stage II colon cancer.39 Multivariate analyses have demonstrated that recurrence scores were associated with risk of tumor

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recurrence and prognostic for outcome independent of conventional clinical and pathologic features. ColoPrint (Agendia) and ColDx (Almac Group, Ltd) are 2 other commercially available assays that

While these assays provide information regarding the risk of recurrence, they also have failed to predict who benefits from chemotherapy. have been demonstrated in smaller validation sets to be prognostic for recurrence risk in stage II colon cancer patients. Similar to Oncotype DX, however, the prediction of recurrence risk for both is independent of other risk factors.40,41 While these assays provide information regarding the risk of recurrence, they also have failed to predict who benefits from chemotherapy. While data may be insufficient to support the use of multigene assays in clinical decisions regarding the role for adjuvant therapy, we must consider that the features that are traditionally used to designate high risk of recurrence in stage II disease (eg, advanced tumor stage, tumor perforation, lymphovascular invasion, postsurgical analysis of fewer than 12 nodes, and poorly differentiated histology) are similarly prognostic but not predictive.42,43 Moreover, tumor grade and lymphovascular invasion are poorly reproduced and have not held up as prognostic factors in some studies. In fact, the Oncotype DX recurrence score provides independent value beyond tumor stage, lymphovascular invasion, number of nodes examined, and tumor grade.39 In our view, it is reasonable to consider the use of these recurrence scores, on a case-by-case basis, for patients with normal-risk stage II colon cancer cases without specific high- or low-risk features.

Applications of Molecular Profiling As our knowledge of genomic data related to cancer has accumulated, the trend has led to the effort to enumerate a comprehensive description of the genomic al-

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terations that define an individual’s tumor. Foundation Medicine and Caris Life Sciences provide 2 of many commercially available next-generation sequencing (NGS) assays marketed as FoundationOne and Molecular Intelligence, respectively. The FoundationOne assay performs deep sequencing of 236 known oncogenic genes, 48 introns, and 19 unique rearrangements, with a list of genes that continues to expand (or contract) with scientific discovery. This set of genes encompasses the usual suspects for all solid tumors and is not tai-

Identification of a potential target does not necessarily mean that a patient benefits from the therapeutic agent that is intended to hit that target. lored to colon cancer. The Molecular Intelligence assay utilizes a variety of techniques, including immunohistochemistry, in situ hybridization, polymerase chain reaction, and NGS, to interrogate either a tumor-specific biomarker panel or a comprehensive gene panel, depending on preference. Both can be performed on formalin-fixed paraffin-embedded clinical samples. In clinical application, these tests may be used to identify therapeutic options that are available through either clinical trial participation or off-label use of a drug approved for another indication. From a cohort of 40 colon cancer specimens analyzed with the FoundationOne assay, 21 (52.5%) were found to have at least one “actionable” alteration associated with potential sensitivity to targeted therapies, including KRAS, BRAF, FBXW7, PIK3CA, BRCA2, GNAS, CDK8, and a novel ALK gene fusion.44 Of course, identification of a potential target does not necessarily mean that a patient benefits from the therapeutic agent that is intended to hit that target. A prospective multicenter study was conducted using the Molecular Intelligence assay to match patients to treatments.45 While 84 of 86 (98%) patients who underwent molecular profiling of their refractory tumors

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had a molecular target identified, only 66 of 84 (78%) went on to receive a treatment according to molecular profiling results. Of these 66 patients, 18 (27%) had a PFS longer than on the regimen on which the patient had previously experienced disease progression. Four of the 11 patients with colon cancer had improvements of PFS ratios ≥1.3. The lack of randomized design, wherein patients were essentially used as their own controls, limits the interpretation of these data. In addition, the ascertainment of its primary end point, PFS ratios, was potentially biased by imprecision in measuring the comparator progression-free interval used to determine PFS ratios as well as lack of blinding. Whether the currently available molecular profiling technologies are sufficiently developed for meaningful clinical impact remains to be prospectively validated. Even so, several academic cancer centers have already launched or are actively engaged in the development of their own institutional molecular profiling panels. At the 2011 ASCO Annual Meeting, investigators from the MD Anderson Cancer Center reported an institutional analysis of up to 11 cancer-associated mutations in tissue for 1144 patients undergoing evaluation for participation in phase 1 clinical trials.46 In 60% of tumors, no mutations were identified. A single mutation was identified in one-third of the tumors. A matched investigational therapeutic option was available for 175 patients (15.3%). In comparison with patients who were treated with unmatched therapies, those patients who received treatment with a matched therapy sustained significantly better response rates (27% vs 5%; P<.0001) and improved median OS (13.4 vs 9.0 months; P=.017). This study is limited by the lack of randomization and its inability to fully distinguish the predictive strength of matched mutational analysis.

Heeding Heterogeneity – What to Biopsy? Heterogeneity across and within tumors remains a considerable barrier to biomarker development. Genomic analyses from a single tumor biopsy potentially underestimate the mutational burden of intratumoral

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heterogeneity, thereby introducing bias into predictive biomarker studies. As an example, Gerlinger and colleagues reported a study of exome sequencing, chromosome aberration analysis, and ploidy profiling in multiple samples obtained from 4 primary renal carcinomas and their metastatic sites wherein intratumoral heterogeneity was observed for multiple tumor suppressor genes, and gene expression signatures varied widely in different regions of the same tumor.47 Variations between the primary tumor and metastatic sites (intertumoral heterogeneity) may also occur with varying frequency, depending on the biomarker of interest. Variation through acquisition or loss of biomarker expression or clonal drift over time (temporal heterogeneity) is also well described.48-50 Speaking to the heterogeneity of colon cancer as a disease and to the inadequacies of our current classification system, researchers presented a new taxonomy of 3 major intrinsic subtypes (A-, B-, and C-type) at the 2013 Gastrointestinal Cancers Symposium. From an unbiased gene expression analysis of 188 colon cancer patients of all stages, this molecular subtype classification was developed and subsequently validated in 543 patients with stage II and III disease. Three subtypes of colon cancer were characterized by unique biologic hallmarks, including epithelial-to-mesenchymal transition, deficiency in MMR genes, and cellular proliferation.51 Patients with A-type or B-type tumors exhibited a more proliferative and epithelial phenotype, better clinical outcomes, and were more likely to benefit from adjuvant chemotherapy. Patients with C-type tumors demonstrated mesenchymal gene expression phenotypes and did not benefit from adjuvant chemotherapy. Moreover, A-type and C-type tumors harbored a higher mutation frequency (4.2% and 6.2%, respectively) versus B-type tumors, which were associated with a low kinome mutation frequency (1.6%) concordant with their mismatch repair deficiency. BRAF mutations were seen in 39% of A-type tumors, 2% of B-type tumors, and 16% of C-type tumors. The development of this single sample predictor portends the eventual classification of colon cancer tumors according to intrinsic

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molecular subtypes that are associated with distinct biology and outcomes and consequently require unique treatment strategies.

Conclusion As we enter into an era of clinical practice accompanied by expanding awareness and availability of NGS and other molecular profiling technologies, we face associated challenges of how to assimilate these technological advances into clinical practice. The market for predictive biomarkers in colon cancer has outpaced

There remains a real risk, however, that the utilization of unvalidated assays outside of the research setting may disadvantage forward progress in this field... our ability to provide sound technical and clinical validation. Similarly, biomarker discovery has not been matched with companion drug discovery.52 As a result, premature implementation of these assays in the clinical setting has led to a healthy degree of skepticism as promises of clinical benefits have failed to mature with time. The application of molecular profiling in our motivated and fit patients with life-threatening cancers who have failed standard therapies is enticing and may serve to reduce the time, expense, and opportunity cost of pursuing clinical trial eligibility without knowledge of biomarker test results. It also may facilitate a small portion of patients to access compassionate use programs for drugs that are in the later stages of development but not yet approved by the FDA for commercial use. There remains a real risk, however, that the utilization of unvalidated assays outside of the research setting may disadvantage forward progress in this field and be counterproductive to the overarching goals of personalized medicine. Whenever a clinical decision is made to give or withhold a standard chemotherapy agent or to recommend participation in a clinical trial of an inves-

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tigational targeted therapy, there is a non-negligible risk of harm to the patient. As an example, early detection of a BRAF mutation in a patient with a new diagnosis of colon cancer may result in a decision to forego standard chemotherapy regimens in favor of participation in a clinical trial of a BRAF-inhibiting therapy; however, this certainly poses a risk of both significant toxicity and lost opportunity to receive conventional therapies if the investigational option proves ineffective. We advocate that the utility of predictive biomarkers must be linked to the treatment strategies whose benefit or risk they predict for. In the climate of increasing molecular testing capabilities, clinicians are urged to approach the commercially available biomarker tests with a healthy level of scrutiny toward clinical validation. We must continue to track and monitor outcomes and individual lessons learned from patients who undergo molecular profiling. At the current juncture, various commercially available assays may be of little added value unless they are studied cohesively with robust investigational therapeutic programs. While early data from clinical applications of molecular assays do suggest that a pairing of mutational analyses with investigational therapeutics may be a practice paradigm for the near future, these data also highlight the need for a seamless interface between predictive biomarkers and their companion drugs. u

References

1. Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374-379. 2. Abrams TA, Meyer G, Moloney J, et al. Patterns of chemotherapy (CT) use in a U.S.-wide population-based cohort of patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2012;30(suppl). Abstract 3537. 3. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703. 4. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010;28:744-752. 5. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626-1634. 6. Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28:466-474. 7. Baselga J, Rosen N. Determinants of RASistance to anti-epidermal growth factor receptor agents. J Clin Oncol. 2008;26:1582-1584.

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8. Khambata-Ford S, Garrett CR, Meropol NJ, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007;25:3230-3237. 9. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663-671. 10. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508-515. 11. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757-1765. 12. Dahabreh IJ, Terasawa T, Castaldi PJ, et al. Systematic review: anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 2011;154:37-49. 13. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408-1417. 14. Benson AB 3rd, Bekaii-Saab T, Chan E, et al. Metastatic colon cancer, version 3.2013: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013;11:141-152. 15. De Roock W, Jonker DJ, Di Nicolantonio F, et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA. 2010;304:1812-1820. 16. Tejpar S, Celik I, Schlichting M, et al. Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab. J Clin Oncol. 2012;30:3570-3577. 17. Loupakis F, Ruzzo A, Cremolini C, et al. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer. 2009;101:715-721. 18. Bertotti A, Migliardi G, Galimi F, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1:508-523. 19. Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M, et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One. 2009;4:e7287. 20. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753-762. 21. Samowitz WS, Albertsen H, Herrick J, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology. 2005;129:837-845. 22. English DR, Young JP, Simpson JA, et al. Ethnicity and risk for colo rectal cancers showing somatic BRAF V600E mutation or CpG island methylator phenotype. Cancer Epidemiol Biomarkers Prev. 2008;17:17741780. 23. Nosho K, Irahara N, Shima K, et al. Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample. PLoS One. 2008;3:e3698. 24. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-337. 25. Bokemeyer C, Van Cutsem E, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48:1466-1475. 26. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377:2103-2114. 27. Ogino S, Shima K, Meyerhardt JA, et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res. 2012;18:890-900.

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28. French AJ, Sargent DJ, Burgart LJ, et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res. 2008;14:3408-3415. 29. Tol J, Dijkstra JR, Klomp M, et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer. 2010;46:1997-2009. 30. Yaeger R, Saltz L. BRAF mutations in colorectal cancer: clinical relevance and role in targeted therapy. J Natl Compr Canc Netw. 2012;10:1456-1458. 31. Kopetz S, Desai J, Chan E, et al. PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol. 2010;28(suppl). Abstract 3534. 32. Corcoran RB, Falchook GS, Infante JR, et al. Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer. J Clin Oncol. 2013;31(suppl). Abstract 3507. 33. Corcoran RB, Falchook GS, Infante JR, et al. BRAF V600 mutant colorectal cancer (CRC) expansion cohort from the phase I/II clinical trial of BRAF inhibitor dabrafenib (GSK2118436) plus MEK inhibitor trametinib (GSK1120212). J Clin Oncol. 2012;30(suppl). Abstract 3528. 34. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100-103. 35. Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227-235. 36. Genomic Health announces worldwide availability of the Oncotype DX colon cancer test [press release]. January 21, 2010. http://investor. genomichealth.com/releaseDetail.cfm?releaseID=439184. 37. O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010;28:3937-3944. 38. Ungefroren H, Groth S, Ruhnke M, et al. Transforming growth factor-beta (TGF-beta) type I receptor/ALK5-dependent activation of the GADD45beta gene mediates the induction of biglycan expression by TGF-beta. J Biol Chem. 2005;280:2644-2652. 39. Venook AP, Niedzwiecki D, Lopatin M, et al. Biologic determinants of tumor recurrence in stage II colon cancer: validation study of the 12gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. 2013;31:1775-1781.

40. Maak M, Simon I, Nitsche U, et al. Independent validation of a prognostic genomic signature (ColoPrint) for patients with stage II colon cancer. Ann Surg. 2013;257:1053-1058. 41. Kennedy RD, Bylesjo M, Kerr P, et al. Development and independent validation of a prognostic assay for stage II colon cancer using formalin-fixed paraffin-embedded tissue. J Clin Oncol. 2011;29:4620-4626. 42. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004;22:1797-1806. 43. Figueredo A, Coombes ME, Mukherjee S. Adjuvant therapy for completely resected stage II colon cancer. Cochrane Database Syst Rev. 2008;(3):CD005390. 44. Ross JS, Lipson D, Sheehan CE, et al. Use of next-generation sequencing (NGS) to detect a novel ALK fusion and a high frequency of other actionable alterations in colorectal cancer (CRC). J Clin Oncol. 2012;30(suppl). Abstract 3533. 45. Von Hoff DD, Stephenson JJ Jr, Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28:4877-4883. 46. Tsimberidou AM, Iskander NG, Hong DS, et al. Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative. J Clin Oncol. 2011;29(suppl). Abstract CRA2500. 47. 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. 48. Diaz LA Jr, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486:537-540. 49. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532-536. 50. Montagut C, Dalmases A, Bellosillo B, et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012;18:221-223. 51. Simon I, Roepman P, Schlicker A, et al. Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT). J Clin Oncol. 2012;30(suppl). Abstract 333. 52. Kelley RK, Atreya C, Venook AP, et al. Predictive biomarkers in advance of a companion drug: ahead of their time? J Natl Compr Canc Netw. 2012;10:303-309.

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Budget Impact Model: Epigenetic Assay Can Help Avoid Unnecessary Repeated Prostate Biopsies and Reduce Healthcare Spending Wade Aubry, MD University of California, San Francisco, California Robert Lieberthal, PhD Thomas Jefferson University, Philadelphia, Pennsylvania Arnold Willis, MD Aureus University School of Medicine, Oranjestad, Aruba Grant Bagley, MD HillCo HEALTH, Washington, DC Simon M. Willis III, MS Aureus University School of Medicine, Oranjestad, Aruba Andrew Layton, BA Quorum Consulting, San Francisco, California

Key Points • Approximately $1.8 billion is spent annually on PSA testing alone, and more than $4 billion is spent on prostate cancer therapies • The AUA has called for new biomarkers for the improved diagnosis and treatment of prostate cancer • Epigenetic assays have been reported to improve the accuracy of prostate biopsies and help to prevent repeated biopsies

rostate cancer is the most frequently detected cancer in men, and 1 of 6 men will be diagnosed with prostate cancer during their lifetime based on Medicare enrollment data.1 In the United States, approximately 19 million men annually are screened

by prostate-specific antigen (PSA) testing,2 resulting in approximately 4.7 million abnormal PSA test results (≥4.0 ng/mL)3 leading to approximately 1.3 million biopsy procedures.4 According to the National Cancer Institute, 241,740 men are diagnosed with prostate

Dr Aubry is Associate Clinical Professor of Medicine at the Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, and Senior Medical Director of Quorum Consulting in San Francisco, California. Dr Lieberthal is Assistant Professor at the Jefferson School of Population Health, Thomas Jefferson University in Philadelphia, Pennsylvania. Dr A. Willis is Associate Dean of Clinical Sciences and Professor of Urology at the Aureus University School of Medicine in Oranjestad, Aruba. Dr Bagley is Senior Advisor, HillCo HEALTH, Washington, DC. Mr S.M. Willis is a third-year medical student at the Aureus University School of Medicine in Oranjestad, Aruba. Mr Layton is Director, Information Technology at Quorum Consulting, San Francisco, California.

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cancer annually, and 28,170 prostate cancerâ&#x20AC;&#x201C;related deaths were reported in 2012.5 Although some forms of prostate cancer are deadly, many forms are low grade and can be managed by active surveillance. Aggressive variants of prostate cancer can be one of the deadliest cancers in men, and accurate diagnosis and follow-up remain a challenge and come at a considerable cost to the US healthcare system.

Clinical Burden Despite the recent controversy that was raised by the US Preventive Services Task Force (USPSTF) findings on PSA testing, leading to their recommendations to stop routine PSA-based screening,6 the American Urological Association (AUA) continues to recommend the PSA blood test, along with digital rectal examination (DRE), for screening men at risk for prostate cancer. Screening has led to a shift of detecting earlier-stage disease, resulting in an increased likelihood for curative treatment. If screening is eliminated, urologists fear an increased incidence of advanced cancers and an increase in healthcare costs to effectively treat these patients.7 Today, urologists typically perform a biopsy for high-risk patients with a rising PSA and for patients with a PSA level â&#x2030;Ľ4.0 ng/mL, obtaining approximately 10 to 12 needle core tissue samples according to the current standard of care.8,9 Of note, an abnormal PSA result can often be caused by factors other than cancer, including infection, inflammation, or other benign conditions such as benign prostatic hyperplasia. This leads to the inclusion of many men with no cancer among those who are being subjected to prostate biopsies (ie, false-positive PSA screening). The rate of cancer detection in men undergoing prostate biopsies is approximately 30%.2,3 An elevated PSA and/or abnormal DRE identifies men at high risk for prostate cancer, and, as a result, many of these men will undergo a biopsy procedure. However, because of the nature of random and limited sampling of the prostate, many cancers are undetected by histopathologic review. Studies by urology and pathology opinion leaders show that initial prostate bi-

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opsy histopathology has a 20% to 30% false-negative rate.8,10,11 Given these reported false-negative rates for histology, many patients with persistently elevated PSA values are at risk for occult cancer. This uncertainty poses a diagnostic dilemma, resulting in many men receiving 2, 3, and sometimes 4 repeated biopsy procedures.12-14

The AUA continues to recommend the PSA blood test, along with digital rectal examination, for screening men at risk for prostate cancer. Repeated biopsies expose patients to the discomfort and risk of complications associated with this invasive procedure. Complications include infections, prostatitis, cystitis, sepsis, endocarditis, hypotension, gastrointestinal hemorrhage, hematuria, and urinary symptoms. Recently, antibiotic resistance has also been cited as a growing concern.1

Economic Burden Repeated biopsies also generate high medical costs. Approximately $1.86 billion is spent annually on PSA tests alone.2,15 More than $4 billion is spent annually on therapies for prostate cancer, and this amount is expected to increase to $8.7 billion by the year 2019.16

Molecular Testing With such high costs to the US healthcare system, as well as negative quality-of-life implications for patients, the AUA has called for new biomarkers for the improved diagnosis and treatment of prostate cancer.17 With the growing movement toward personalized medicine, the application of molecular testing to improve cancer detection and the management of patients represents an evolution in oncology.2,18 Epigenetic assays, in particular, have been reported to improve on the accuracy of prostate biopsies and histopathologic review.2,8 (Epigenetic refers to gene regulatory mechanisms; epigenetic assays are based on

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the differences in the chromatin structure of active and silent genes.) In a recent multicenter blinded study, such an epigenetic assay (ie, ConfirmMDx for Prostate Cancer) was used to detect occult cancer in histopathologically negative prostate biopsies.8 The assay was performed using multiplex methylation-specific polymerase chain reaction to assess the DNA methylation status of the GSTP1, APC, and RASSF1 genes associated with the presence of cancer in residual negative prostate biopsy tissue samples.3,8,10 Using this advanced molecular diagnostic test allows for a higher degree of accuracy that was previously unattainable through prostate biopsy procedures alone.

The cost analysis was based on total costs of 1 year in the course of prostate cancer screening and evaluation through prostate biopsy. By detecting epigenetic changes in cancer lesions or in neighboring cells (ie, field effect) that are known to be associated with oncogenesis progression, these biomarkers aid in the identification of occult prostate cancer. This field effect accounts for improved detection in adjacent benign-looking tissue, providing a higher negative predictive value than standard histopathology alone.19,20 The test results of this new epigenetic assay can guide urologists in decisions regarding the need to repeat a biopsy in patients with a previously negative biopsy who are still considered at risk for prostate cancer.8

A Budget Impact Analysis A budget impact model was developed to assess whether the epigenetic assay can also produce financial benefits beyond the reported clinical and health benefits. The model was designed to quantify the impact on the costs associated with repeated biopsies used for the screening and diagnosis of prostate cancer and to test the hypothesis that the epigenetic assay produces a beneficial reduction in costs to commercial health plans while providing improved guidance for patient man-

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agement that leads to less invasive and less costly care. This type of analysis is an essential tool for healthcare managers and policymakers budgeting and instituting coverage decisions for prostate cancer diagnostics.

Methods Study Design The budget impact model is presented from the perspective of a hypothetical commercial health plan, and direct costs are calculated over a 1-year time horizon using Medicare fee-for-service (FFS) rates.21,22 The membership of this health plan is based on an assumed size of 1 million members, half of whom are males. The membership is distributed among age categories according to US population data.23 The model’s base case analysis was conducted for a hypothetical plan using patient age groups between 40 and 64 years (similar to those in commercial health plans). An additional sensitivity analysis was conducted for a hypothetical plan consisting of patients aged ≥65 years (similar to a Medicare health plan), using methods identical to the base case, with the exception of the patient ages and corresponding PSA rates. Biopsies and costs for patients younger than age 40 years or older than age 74 years were not included in the analysis. The model screens the population to select patients who may receive a biopsy to test for the presence of prostate cancer. It then selects a specific subpopulation of those men – individuals who may receive a repeat biopsy. For men at risk of undergoing a repeated biopsy, the model allows for the simulation of the current (reference scenario) and a counterfactual reality (new scenario). In the reference scenario, the model uses current clinical patterns of care to simulate the treatment of men at risk of prostate cancer; a molecular assay was not utilized for prostate cancer detection. In the new scenario, men at risk for a repeat biopsy are evaluated with the epigenetic assay, and those with a negative DNA methylation test result are spared a repeat of the biopsy, thereby reducing the number of unnecessary procedures. The cost analysis was based on total costs of 1 year in the course of prostate cancer screening and evaluation

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through prostate biopsy. Costs to the health plan are assumed to be equal to the Medicare FFS rates, which provide a conservative benchmark for reimbursement rates paid by other health plans. In the reference scenario, the health plan incurs the costs of one or several repeated biopsies and the associated iatrogenic costs. In the new scenario, the health plan incurs the cost of an additional diagnostic test performed on the residual prostate tissue from the original sample plus the cost for repeated biopsies and associated iatrogenic costs on patients who had positive test results. The model assumes that the epigenetic assay would be used for all men meeting the assayâ&#x20AC;&#x2122;s eligibility requirements, including an abnormal DRE, an elevated PSA level, and a negative prostate biopsy. Both scenarios calculate a total cost and a plan budget impact, expressed on a per-member per-month (PMPM) basis, as well as the aggregate annual cost to the plan. Data Sources The PubMed database was searched for published clinical and pharmacoeconomic studies to assign values to the clinical and cost parameters used in the model. Studies were identified in PubMed that reflect current practice patterns of 10 to 12 core prostate biopsies in contrast to older studies that were based on sextant biopsy practice. For cost parameters, a combination of published literature cross-referenced to Medicare payment rates was used. Parameters pertaining to the accuracy and outcomes of the assay (including the assayâ&#x20AC;&#x2122;s sensitivity and specificity, and the positive and negative predictive values) were cited from the MATLOC clinical trial.8

Figure. Potential Patients for Epigenetic Assay in a 1-Million-Member Health Plan Members in commercial health plan (age, 0-64 yrs) N = 1 million Excluded patients 500,000 females Male patients (all ages) N = 500,000 Excluded men (age <40 yrs) N = 313,502 Male patients (age, 40-64 yrs) N = 186,498 Excluded patients 145,301 not screened (PSA) Number of men screened (PSA) N = 41,197 Excluded patients 38,396 did not have prostate biopsy Men who had prostate biopsy N = 2801 Excluded patients 700 diagnosed with prostate cancer Men at risk for repeated biopsy N = 2101

PSA indicates prostate-specific antigen. Sample Selection PSA screening rates in US males vary by age, ranging from approximately 8% to almost 50%.24 Of all men screened for PSA, 6.8% are assumed to undergo biopsy based on a PSA of at least 4 ng/mL.25 These PSA and biopsy rates were applied to the hypothetical commercial health plan. Of the hypothetical plan, patients aged 40 to 64 years were selected, using demographic data

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from the US Census Bureau 2010, for inclusion in the model. Applying the national PSA screening and biopsy rates to the hypothetical commercial population yields a total of 2801 men undergoing a prostate biopsy. A total of 2101 men were deemed at risk for repeated biopsy based on a prostate cancer detection rate of 25% (Figure).25

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Table 1. Diagnostic Accuracy of the Epigenetic Assay Variable

Rate

Initial biopsy false-negative rate

0.18

Multiplex DNA Methylation Epigenetic Assay Sensitivity

0.68

Specificity

0.64

Negative predictive value

0.90

Positive predictive value

0.29

Total Men at Risk for a Repeated Biopsy This budget impact analysis compares the proportion of the 2101 men in the cohort who are at risk for a repeated biopsy in 2 potential scenarios – the reference scenario and the new scenario, which is using the epigenetic assay. In the reference scenario, many patients with rising or elevated PSA levels will be seen again for DRE or PSA testing and be considered for a repeated biopsy. In this standard of care, 43% (903) of the patients with a histopathologically negative biopsy are referred for a repeated biopsy based on persistent clinical risk factors.13 In the new scenario, these same patients are triaged with the epigenetic assay. In the new scenario, 3% of

patients would not be eligible for the epigenetic assay because of atypical small acinar proliferation (ASAP) found in their previous biopsy tissue.12 The model assumes that patients with ASAP will receive a repeated biopsy, given the high risk of prostate cancer associated with this histopathologic finding. Approximately 99.9% of all cases would have sufficient tissue for this epigenetic assay, leaving 875 evaluable cases (based on 2 quality-not-sufficient cases of 749 in laboratory experience, through November 30, 2012, when the data were collected). The Epigenetic Assay The multiplex DNA methylation epigenetic assay became available in the United States in May 2012 (through MDxHealth’s CLIA-certified, CAP-accredited laboratory in Irvine, CA). The performance characteristics of this assay (Table 1) were described in the MATLOC clinical trial, which investigated the clinical utility of this assay.8 These characteristics were used in our budget impact model to determine the anticipated number of patients who would be identified as positive or negative for methylation markers. The test is designed such that its high (90%) negative predictive value accurately distinguishes the pa-

Table 2. Men at Risk for Repeated Prostate Cancer Biopsy Reference Scenario (standard of care)

New Scenario (epigenetic assay)

2101

Men referred for repeated biopsy or methylation test, %

Number of men referred for repeat biopsy or methylation test, N

903

N/A

99.9

Evaluable cases, N

N/A

875

Cases with positive methylation markers, N

N/A

365

Cases with negative methylation markers, N

N/A

510

903

366

Variable Men at risk of repeated biopsy, N

Number of men with ASAP, % Cases with sufficient tissue for methylation test, % Risk stratification based on methylation markers

Total men referred for repeated biopsy, N ASAP indicates atypical small acinar proliferation; N/A, not applicable.

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tients with negative prostate biopsies from patients who may have occult cancer.8 In the budget impact model, under the reference scenario, 43% (903) of men at risk for repeated biopsy were referred for repeated biopsy. In the new scenario, testing the high-risk patients with the epigenetic assay significantly reduced the number of repeated biopsies by confirming the histopathologically negative biopsy results for 510 men. The epigenetic assay identified 366 men with positive DNA methylation results who would be referred for repeated biopsy (Table 2). Model Variables and Assumptions Conservative assumptions were made as to the number of repeated biopsies based on reported rates. In the standard of care, 43% of men are referred to have 1 repeated biopsy, 44% of whom have a second biopsy, and 43% of these have a third biopsy. The 100% of men tested with the epigenetic assay who are methylation-positive were assumed to receive a repeated biopsy. A total of 1472 repeated biopsies are expected to be performed in the reference scenario compared with only 366 repeated biopsies with the epigenetic assay in the new scenario. The average cost of a prostate biopsy procedure is $1946, which is a conservative estimate based on decreased interim 2013 Medicare Physician Fee Schedule rates; this does not take into account prophylactic antibiotic, pain, or other concomitant medication costs.25 The total expected complication costs per patient for an initial or repeated biopsy were calculated using Surveillance, Epidemiology and End Results (SEER)-Medicare cancer registries’ reported incidence of infectious and noninfectious complications and the associated mean payment for the Medicare Severity-Diagnosis Related Groups (MS-DRGs) from the 2012 Centers for Medicare & Medicaid Services MS-DRG payment schedule.22 Table 3 shows the calculations for the average cost ($392) of complications per patient undergoing repeated prostate cancer biopsy. The total weighted cost of a fully burdened biopsy is $1946 – the sum of the

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Table 3. Per-Patient Costs Associated With Biopsy Complications Infectious complications

DRG Payment, $

Kidney infection

5594

Urinary tract infection

5594

Prostatitis

6220

Cystitis

5594

Sepsis/bacteremia

16,662

Endocarditis

10,943

Hypotension

5801

Average payment for infectious complications

8058

Incidence (SEERMedicare)

PerPatient Cost, $

0.04

322

0.012

Noninfectious complications Gastrointestinal hemorrhage

6559

Hematuria

5366

Acute posthemorrhagic anemia

5660

Urinary symptoms/ retention

5594

Average payment for noninfectious complications

5795

Total cost

392

DRG indicates diagnosis-related group; SEER, Surveillance, Epidemiology and End Results. procedural cost and the cost of complications weighted by incidence. The retail price for the epigenetic assay is $206 per individual core, or $2060 for a 10-core biopsy (pricing is based on the cost of the ConfirmMDx for Prostate Cancer Test, as provided by MDxHealth, the manufacturer of this test). The model assesses the health plan’s costs compared with billed charges; therefore, the cost of this assay is discounted by 10%, to conservatively reflect payer costs, at $1855.02 per test.

Results Costs This budget impact analysis demonstrates that the

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Table 4. Total Resource Use: Repeated Prostate Biopsies Resource

Reference Scenario New Scenario (standard of care) (epigenetic assay)

Total men referred for first repeated biopsy, N

903

Total men referred for second repeated biopsy, N

397

Total men referred for third repeated biopsy, N

171

Total epigenetic tests, N Total repeated biopsies, N Total repeated biopsies avoided, N

903

875

1472

366 1106

net cost to a commercial plan is lower if patients undergoing prostate cancer biopsies are managed using the assay. Although this involves an additional cost for the acquisition of the assay, using the assay results in a reduction of 1106 unnecessary biopsies for a health plan with 1 million members (Table 4). The total cost of repeated biopsies avoided is $2,152,276 (1106 biopsies avoided × $1946 per biopsy). The total cost to the health plan in 1 year was calculated to be $2,864,142 in the reference scenario versus $2,333,341 with the epigenetic assay in the new scenario. To calculate the total diagnostic cost per patient in the reference scenario, the cost of a prostate biopsy ($1946) was applied and weighted to a repeated biopsy distribution rate for the percentage of men who receive first, second, and third repeated biopsies of 43%, 44%, and 43%, respectively.13 For the new scenario, the total diagnostic cost per patient includes the cost of the assay plus the weighted biopsy cost, applied and weighted to 43% of men who have positive results based on the epigenetic assay (based on the sensitivity, specificity, and negative and positive predictive values).8 The total diagnostic cost

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per patient was $3172 in the reference scenario compared with $2584 in the new scenario, resulting in a savings of $588 per patient managed. This results in a total savings of $530,801 annually to the health plan, or –$0.0442 PMPM (Table 5). Sensitivity Analysis To test for uncertainty among the model parameters, all calculations were repeated for a patient population of men aged ≥65 years, representative of the Medicare population. Patients older than age 74 years were excluded from the model, resulting in an at-risk cohort of 6917 men. Testing these patients with the assay resulted in a reduction of 3642 unnecessary biopsies. The total cost of repeated biopsies avoided was $7,086,416. The total cost to the plan in 1 year was $9,429,097 in the reference scenario and $7,688,849 in the new scenario. This resulted in a total budget impact of –$1,740,248 to the plan, or –$0.1450 PMPM. The total diagnostic cost per patient was $3172 in the reference scenario compared with $2584 in the new scenario (Table 6), resulting in a savings of $588 per patient managed.

Discussion The budget impact model was developed to evaluate the clinical and financial benefits of payer coverage for the epigenetic assay based on well-founded and conservative assumptions from existing evidence and current standards of care for patients considered at risk for prostate cancer. The analysis demonstrates that a commercial health plan would realize cost savings with the coverage of the epigenetic assay. The up-front cost of the epigenetic assay will be recovered based on the savings associated with avoided biopsy procedures and associated complications of biopsies. Given these assumptions and the costs associated with the current standard of care, the inclusion of the epigenetic assay into the management of men who are screened for prostate cancer would result in a net cost savings of $530,801 in the first year after the assay became available in the

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Table 5. Total Annual Costs and Budget Impact: Reference Scenario Versus New Scenario Reference Scenario (standard of care)

New Scenario (epigenetic assay)

Total Annual Cost, $

PMPM Cost, $

Total Annual Cost, $

PMPM Cost, $

Total cost of epigenetic assay

1,623,143

0.14

Total cost of repeated biopsies

2,864,142

0.33

710,198

0.06

2,152,276

0.18

2,864,142

0.24

2,333,341

0.19

3172

0.24

2584

0.19

Cost

Total cost of repeated biopsies avoided Total diagnostic cost to health plan Total diagnostic cost per patient Total budget impact to plan

–530,801

Total budget impact to plan PMPM

–0.442

PMPM indicates per member per month.

Table 6. Sensitivity Analysis: Total Costs and Budget Impact Reference Scenario (standard of care)

New Scenario (epigenetic assay)

Total Annual Cost, $

PMPM Cost, $

Total Annual Cost, $

PMPM Cost, $

Total cost of epigenetic assay

0.00

5,346,168

0.53

Total cost of repeated biopsies

9,429,097

1.09

2,342,681

0.27

Cost

Total cost of repeated biopsies avoided Total diagnostic cost to health plan Total diagnostic cost per patient

0.00

7,086,416

0.82

9,429,097

1.09

7,688,849

0.81

3172

0.33

2584

0.24

Total budget impact to plan

–1,740,248

Total budget impact to plan PMPM

–0.1450

PMPM indicates per member per month.

United States in a health plan with 1 million members. The epigenetic assay provides clear and actionable results that aid the urologist in treatment decision making, improving patient care, and yielding significant healthcare savings. A key assumption is that a health plan inclusion of the epigenetic assay in medical policy and coverage decisions will motivate a change in the behavior of urologists, resulting in a reduction of repeated biopsies. Policy tools that promote appropriate patient management according to evidence-based guidelines, such as value-based payment (eg, financial incentives for choosing evidence-based in-

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terventions) or coverage restrictions for repeated biopsies, may further enhance such outcomes.

Limitations The results of this budget impact analysis are based on a hypothetical cohort modeled on the basis of values from the published literature. The use of national averages may not reflect the true variety in clinical practice. Initial prostate biopsy and repeated biopsy rates in specific geographic regions may be higher or lower than the reported national averages. Costs and resource

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utilization may also vary between practices and between geographic regions. Another potential limitation to the application of this model is that the future rates of screening for prostate cancer may vary, given the recent recommendation of the USPSTF to stop routine PSA-based prostate cancer screening.6 The recommendation suggests that physicians discuss the benefit-risk ratio with their patients and decide if PSA testing is appropriate based on risk factors such as race or family history.6 How this will affect screening rates is not yet known and is not explored in this analysis.

This study is intended to address the financial impact of the epigenetic assay on the costs to commercial health plans of repeated biopsies. This study is intended to address the financial impact of the epigenetic assay on the costs to commercial health plans of repeated biopsies. Because the cost impact is associated with a reduction in complications from the biopsy, the study provides some perspective on the impact of the assay on clinical outcomes. However, clinical outcomes were not evaluated in the design of the present study. A cost-effectiveness analysis would be the suitable approach to investigate the cost and the clinical outcomes associated with the use of the assay. In addition, the assayâ&#x20AC;&#x2122;s impact on the rates of prostate cancer diagnosis and earlier case identification were outside the scope of the study and were not methodically investigated. Subgroup analyses were not performed for modestly elevated PSA patients versus those with markedly elevated PSA because these patients are not managed differently in clinical practice. Because of the negative predictive value of 90% of the epigenetic assay, 10% of patients testing negative with the assay could have a diagnosis of prostate cancer identified through recommended return screening. The clinical impact of this is not evaluated by the design of

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this model. The test has only been commercially available in the United States since May 2012.

Conclusion Approximately $1.8 billion is spent annually on PSA testing alone, and more than $4 billion is spent on prostate cancer therapies, leading the AUA to call for new biomarkers to improve accurate diagnosis and reduce the cost burden. Epigenetic assays have been reported to improve the accuracy of prostate biopsies and help to prevent repeated biopsies, the majority of which show negative results. Based on a recent analysis, the results of a new epigenetic assay can guide urologists in decisions regarding the need to repeat a biopsy in patients with a previously negative biopsy who are still considered at risk for prostate cancer. A budget impact analysis calculated whether this assay can also produce financial benefits beyond the previously reported clinical benefits. Using a hypothetical health plan with 1 million members, this analysis shows that the total annual cost to the health plan would be reduced if patients with histopathologically negative biopsies would be managed with the epigenetic assay. Specifically, the use of the assay would reduce the number of repeated biopsies from 1472 to 366, thereby preventing 1106 unnecessary biopsies and reducing the annual costs by approximately $500,000 to the health plan based on the current standard of care. This test has only been available for a short time. Research to investigate the clinical impact of this assay based on real-world data is appropriate. u Disclaimer At the time this study was submitted for publication, prostate biopsy costs incorporated maximum payment reductions; conversion factor $25.0008 per the 2013 Medicare Physician Fee Schedule published December 5, 2012. If changes to the sustainable growth rate patch and sequestration cuts occur, savings for payers reimbursing the epigenetic assay may be greater than reported.

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Oncology

June 2013

Pharmacoeconomics

Stakeholder Perspective

Molecular Epigenetic Tests Can Improve Clinical Outcomes While Reducing Healthcare Costs Kelly Huang, PhD

Health Plans Health insurance plans and other payers recognize the potential for molecular diagnostics to facilitate the approach known as personalized medicine, which utilizes molecular testing to identify patients who will benefit from a specific approach to management or a specific targeted therapy. Personalized medicine can lead to reduced healthcare costs over the life of the patient. However, payers are struggling to keep up with the rapidly expanding range of molecular tests. Because of the ambiguous nature of “laboratorydeveloped tests,” many health insurers are deeming many new tests as experimental or investigational and are therefore refusing to cover them. When determining coverage of molecular diagnostic tests, payers expect evidence not only for clinical utility but also for cost-effectiveness.1 It follows that cost-effectiveness should also lead to a reimbursement structure that is based on the value of that test or service rather than merely on stacking codes of the methodology steps. In this current article by Aubry and colleagues, the authors propose a well-articulated hypothetical model to assess the value of an epigenetic test’s (ConfirmMDx) ability to confirm the negative results of a prostate biopsy. According to this model, using this test leads to a meaningful $588 savings per patient managed by avoiding unnecessary repeated prostate biopsies. As with any hypothetical model, there are limitations to the analysis with regard to real-world facts. Nevertheless, the authors clearly outline their assumptions and the rationale behind their calculations so readers can consider the conclusions, assess the sensitivity of the assumptions, and arrive at their

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own perspective. Beyond the economic benefits of this test, payers should also consider the improvement in quality of life for patients who avoid the need for repeated biopsies.

Patients/Providers Patients and providers will experience the benefits of many new and soon to become available advances in the detection and treatment of prostate cancer. Along with new drug therapies and surgical advances, such as minimally invasive ablative procedures, molecular epigenetic tests show promise in determining the aggressive nature of a tumor, or in the case of ConfirmMDx, provide true confirmation of negative biopsy results. Although these epigenetic tests are relatively new, they already provide further input, along with the details of the biopsy results, prostate-specific antigen history, family history, digital rectal examination, age, and so on, to help the physician’s and the patient’s determination of a specific treatment regimen. Over time, as more experience is gained and the tests are improved for specificity and sensitivity, molecular epigenetic tests can be expected to provide significant improvements in extended survival and enhanced quality of life for patients. u

Disclosure Kelly Huang, PhD, is president of HealthTronics, maker of ConfirmMDx and other epigenetic tests for prostate cancer.

Reference

1. Trogan G. What do payers want in oncology diagnostics? Insights from a national survey of top commercial and Medicare health plans. Am Health Drug Benefits. 2011;4(4 Special Issue):34.

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Author Disclosure Statement Dr Aubry is a Consultant to MDxHealth. Dr Lieberthal receives research/grant support from Abbott Molecular, Genomic Health, and MDxHealth. Dr A. Willis is a Consultant to ConfirmMDx and 21st Century Oncology and is on the Speaker’s Bureau for Astellas, Clinlogix, GlaxoSmithKline, Eli Lilly, and sanofi aventis. Dr Bagley is a Consultant/Advisor to HillCo Health. Mr Layton is a Consultant to ConfirmMDx. Mr S.M. Willis has nothing to disclose. Reprinted with permission from Aubry W, et al. Am Health Drug Benefits. 2013;6(1):15-24. © 2013 Engage Healthcare Communications.

References

1. Loeb S, Carter HB, Berndt SI, et al. Complications after prostate biopsy: data from SEER-Medicare. J Urol. 2011;186:1830-1834. 2. Ekwueme DU, Stroud LA, Chen Y. Cost analysis of screening for, diagnosing, and staging prostate cancer based on a systematic review of published studies. Prev Chronic Dis. 2007;4:A100. 3. Van Neste L, Herman JG, Otto G, et al. The epigenetic promise for prostate cancer diagnosis. Prostate. 2012;72:1248-1261. 4. Mosquera J-M, Mehra R, Regan MM, et al. Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res. 2009;15:4706-4711. 5. National Cancer Institute. Surveillance, Epidemiology and End Results. 2012. http://seer.cancer.gov/csr/1975_2009_pops09/results_single/ sect_01_table.01.pdf. Accessed November 1, 2012. 6. US Preventive Services Task Force. Screening for Prostate Cancer. May 2012. www.uspreventiveservicestaskforce.org/prostatecancerscreen ing/prostatefinalrs.htm. Accessed September 20, 2012. 7. Crawford D, Grubb R, Pinsky P, et al. Factors influencing initial treatment decisions in PLCO: comparison of screening and control arms. Abstract LBA4. Proceedings of the AUA Annual Meeting, May 21, 2012; Atlanta, GA. 8. Stewart G, Van Neste L, Delvenne P, et al. Clinical utility of an epigenetic gene to detect occult prostate cancer in histopathologically negative biopsies: results of the multicenter MATLOC study. J Urol. 2013;189:1110-1116. 9. Kehinde EO, Al-Maghrebi M, Sheikh M, et al. Combined ciprofloxacin and amikacin prophylaxis in the prevention of septicemia after transrectal

ultrasound guided biopsy of the prostate. J Urol. 2013;189:911-915. 10. Trock B, Brotzman MJ, Mangold LA, et al. Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies. BJU Int. 2012;110:56-62. 11. Rabets JC, Jones JS, Patel A, et al. Prostate cancer detection with office based saturation biopsy in a repeat biopsy population. J Urol. 2004;172:94-97. 12. Laurila M, van der Kwast T, Bubendorf L, et al. Detection rates of cancer, high grade PIN and atypical lesions suspicious for cancer in the European Randomized Study of Screening for Prostate Cancer. Eur J Cancer. 2010;46:3068-3072. 13. Pinsky PF, Crawford ED, Kramer BS, et al. Repeat prostate biopsy in the prostate, lung, colorectal and ovarian cancer screening trial. BJU Int. 2007;4:775-779. 14. Resnick MJ, Lee DJ, Magerfleisch L, et al. Repeat prostate biopsy and the incremental risk of clinically insignificant prostate cancer. Urology. 2011;77:548-552. 15. National Cancer Institute Trends Progress Report-2009/2010 Updated. www.cancer.gov/newscenter/newsfromnci/2010/ProgressRe port2010. Accessed November 1, 2012. 16. Merril J. Prostate cancer market snapshot: more than provenge. The Pink Sheet. November 22, 2010. Elsevier Business Intelligence Publications and Products. www.elsevierbi.com/Publications/The-Pink-Sheet/72/47/ Prostate-Cancer-Market-Snapshot-More-Than-Provenge?resu lt=2&total=2&searchquery=%253fq%253dProstate%252520Can cer%252520Market%252520Snapshot%2526date%253don%25253a11 %25252f22%25252f2010. Accessed January 29, 2013. 17. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177:2106-2131. 18. Stricker S. The era of personalized medicine in oncology: novel biomarkers ushering in new approaches to cancer therapy. Am Health Drug Benefits. 2011;4:387-388. 19. Mehrotra J, Varde S, Wang H, et al. A quantitative, spatial resolution of the epigenetic field effect in prostate cancer. Prostate. 2008;68:152-160. 20. Trujillo KA, Jones AC, Griffith JK, et al. Markers of field cancerization: proposed clinical applications in prostate biopsies. Prostate Cancer. 2012;2012:302894. 21. Centers for Medicare & Medicaid Services. Medicare Physician Fee Schedule 2013. www.cms.gov/Medicare/Medicare-Fee-for-Service-Pay ment/PhysicianFeeSched/index.html?redirect=/physicianfeesched/. Accessed December 5, 2012. 22. Centers for Medicare & Medicaid Services. Medicare Inpatient Prospective Payment System 2012. www.cms.gov/Medicare/Medicare-Feefor-Service-Payment/AcuteInpatientPPS/index.html. Accessed December 5, 2012. 23. US Census Bureau. Age and sex composition: 2010. 2010 census briefs. www.census.gov/prod/cen2010/briefs/c2010br-03.pdf. Accessed November 1, 2012. 24. Drazer MW, Huo D, Schonberg MA, et al. Population-based patterns and predictors of prostate-specific antigen screening among older men in the United States. J Clin Oncol. 2011;29:1736-1743. 25. Nichol MB, Wu J, An JJ, et al. Budget impact analysis of a new prostate cancer risk index for prostate cancer detection. Prostate Cancer Prostatic Dis. 2011;14:253-261.

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The Last Word

Trouble at the Beginning: Diagnostic Acumen and the Relentless Search for Red Flags

causes of patient maladies. The practical consequences our decades ago I was told that pain is the univerclearly undermine care that is evidence based, value sal magnet drawing people to a doctor’s care. At based, and patient centered…what could be better? the time, it was medical wisdom itself – for who Fighting this process is population-based medicine, would seek aid unless pain suggested a health issue? Towhich in comparison is the mediocrity day’s personalized medicine, technoof going through the motions, followlogically driven to include preventive ing an algorithm even when expecare, has updated this maxim, whose rience has demonstrated the futility fundamental point was to address paof the ensuing treatment strategy. If tient reluctance to seek medical care the treatment is not succeeding, if even in the presence of pain, not solely the condition persists, it follows that because of it. This makes medical difthe diagnosis is likely wrong and the fidence health’s greatest enemy. The determination to prevail over sickmaxim fundamentally demanded a proness has died with it. This kind of active fervor toward fighting disease, clinical failure is the product of a using all available means to succeed. If healthcare system that is transaction a gap still exists in this model, it is in Robert E. Henry based, its clinicians acceding to popdiagnosis, based on knowing the cause ulation-based diagnostic algorithms of a patient’s disease. Our healthcare incapable of giving the “last word” on what’s ailing the system will remain poles apart from a wellness-based, patient. Return for a moment to Hollywood, which not personalized medicine model until physicians deteronly finds fame in celebrities like Angelina Jolie but mine to make diagnostic excellence a hallmark of their also gave us what a brilliant medical authority refers care, treating patients with a solid understanding of the to as an enjoyable “medical fantasy,” the television sedisease pathophysiology. ries House. The series features patients presenting with Proactive medical care, understanding what is truly obscure and misleading symptoms that do not respond at the core of any malady, is the mantra of personalto population-based algorithmic averages. Where the ized medicine in cancer. Showcasing this with all the series diverges from mainstream practice is in the hedazzle of celebrity attention was actress Angelina Joroic efforts Dr House and his team make at collabolie’s highly publicized double mastectomy, proactively rative thinking to come up with the real diagnosis… administered before pain or tumor could signal that and where that is accurate, the cure is not far behind. the BRCA1 gene mutation she carries had made her a Their MO: looking for any red flags that the body has breast cancer victim. This is patient screening and dicleverly hidden in a sea of red herrings. Determined not agnostic wellness-based healthcare at its finest, demonto yield to the law of averages, they continue to listen strating responsibility of patient and physician alike to for not just zebras, but antelopes or anything that galknow the nature of that which is afflicting the person… lops, rather than just horses when they hear hoof beats. in this case, even before she became a patient. Resourcefulness, born of a practical humility before the This has placed diagnosis on the pedestal of medicine blazing mysteries of the human body, drives their search for all to admire and emulate. But experience shows a for what’s causing the illness. Often outrageous, House widespread climate of physician indifference to root

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is never smug, just determined to fight for any chance that he can find. Knowing the diagnosis is to know the disease pathophysiology, and with it, the patient, in a true personalized medicine rescue from a condition cleverly posing as something else. In cancer, a major offender of poor diagnosis is breast cancer, examined immediately below. In chronic noncancer pain (CNCP), patient screening and diagnosis became so disastrously inadequate as to motivate a major initiative from the Institute of Medicine (IOM), a 340-page treatise on the problem of this form of pain – a useful analogue in understanding the significance of diagnostics to personalized medicine in cancer care – and throughout the healthcare system. I first address cancer from a legal liability standpoint, instructive in establishing how a jury holds physicians liable for a thorough, timely, and accurate diagnosis and referral process, as demonstrated in a panel recently convened by a major legal group, The Doctors Company. The panel’s findings revealed that breast cancer accounts for the majority of cancer-related lawsuits, and it identifies numerous tactical aspects of responsible physician care at the diagnostic phase of management. It showed that diagnosis is weak for several reasons. Patients find a lump before physicians do; breast lesions cannot be adequately evaluated by palpation or mammography alone; physicians often fail to seek biopsies based on the findings of a mammogram; the mammogram is a clumsy diagnostic tool, often generating false-negative readings; physicians often attempt to evaluate their own radiologic tests rather than submitting them to other qualified experts, allowing lesions to go undetected; comorbidities can obscure an underlying condition, making thoroughness the reigning principle of diagnostic activities; physicians are found negligent if they fail to provide their pathologist a thorough background/context for the biopsy; if a sharp discord exists between the histologic results of the biopsy and the clinical impression, the physician must show why, perhaps requesting an additional biopsy, until the biopsy and clinical impression make sense; courts find physicians responsible for the timeliness of the diagnosis, avoiding

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any delays in establishing a diagnosis that would prevent a virulent cancer from spreading; physicians are held liable if they fail to conduct a costly CAT scan for a patient with headaches, when the scan could prevent a diagnosis of a deadly tumor or aneurysm; referrals must be handled with complete follow-through, even if patients dislike a specialist to whom they are referred; similarly, physicians are responsible for keeping track of their patients and following through with the results of tests and referrals; patient reluctance to take prescribed tests because of cost must not be accepted, or the physician will be held liable; accuracy of the diagnosis is as important as its timeliness, with the physician liable for

If the public and the courts take cancer diagnosis and treatment seriously, improvements in CNCP and all of medicine cannot be far behind. getting the diagnosis right; and curiously, juries often hold the physician responsible for negligence if a patient does not show up for scheduled tests or follow-up and the physician fails to make an effort. The composite picture shows how central diagnosis is in the court of law. The public demands proactive physician behavior to ensure an accurate and treatment-relevant diagnosis – they do not put the responsibility for this commitment to vigilance on the patient, but on the physician. CNCP is an analogue from outside the walls of oncology, underscoring the need to prioritize diagnostic excellence in the expanse of personalized medicine elsewhere. This enigmatic disease state is only lately beginning to receive some of the respect accorded patients with cancer-related pain, thanks largely to the efforts of the IOM to change the cultural outlook that stigmatizes patients for a condition that requires opioid treatment. This textbook case of clashing stakeholder agendas provides a gap analysis of diagnosis and real-world care. If the public and the courts take cancer diagnosis and treatment seriously, improvements in CNCP and all of medicine cannot be far behind. An example of meager

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diagnostic efforts for CNCP involves knowing whether it involves misaligned vertebrae – an assumption clinicians often make – or any of the spondylitis conditions: ankylosing spondylitis, axial spondylitis, or undifferentiated spondylitis. Referring such a patient to a chiro-

Now a celebrity has gone public with a vindication of personalized medicine and the diagnosis that prevented the cancer in question from forming.

SAVE DATE

practor to align the vertebrae would be disastrous, since ankylosing spondylitis may involve vertebral fusion and manipulation would break a fused spine! There is growing interest in this offshoot of rheumatoid arthritis, but one wonders how many physicians know that April is Spondylitis Awareness Month. But they will, as they increasingly attach significance to diagnosing CNCP. The point of this demonstration is to show the consequences of weak physician knowledge of root causes at the diagnostic phase of medicine. As in cancer, CNCP can stem from a myriad of causes; ankylosing spondylitis can mimic other disease states. Yet there is far more

intense interest in pain management from the Drug Enforcement Administration, which views CNCP as a gateway for opioids, than from physicians. This interferes with diagnostic interest in the complex problem of pain pathogenesis, and medicine’s priorities must not be intimidated by crime enforcement activities. Diagnostics are a major component of personalized medicine in oncology – as it is in all healthcare conditions. Personalized medicine comes to life at the diagnostic juncture. The IOM report on CNCP reminds us of a dangerous condition of deflecting physician interest in diagnostics. They must embrace diagnostics to find the red flags that prevent appropriate, personalized care. Pretechnology medicine relied on pain that drove patients to their physicians for diagnosis. Now a celebrity has gone public with a vindication of personalized medicine and the diagnosis that prevented the cancer in question from forming. This is a triumph over indifference that must continue to gather momentum until it typifies physician and patient prioritizing of diagnostic practices.

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Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

cancer.1 More than half are living well beyond 5 years ancer is an illness associated with substantial physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. 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SECOND ISSUE IN THE 2013 Therapy SERIES to Cancer ce en er SE C O N dh Nona D ANN Impact of UAL

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Introduc tion to O ncology Pain Ma nageme nt

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ers effectiv teeth. Iâ&#x20AC;&#x2122;m betwee age pain ass ely manociated wit was how peo sure back in the day n its treatm h cancer and this ent quor to numple coped with pain provide you . The following art â&#x20AC;&#x201C; icle hard to bite b them and someth limation ass with a wealth of inf s ing on. ociated wit orToday all This is far from ideal. and guidel h these too ine hospital env patients who ent that though s. They also promo ls er a tful care be an inpatie ironment, whether te sure that nt it Lillie D. Sho all of us add taken to entheir doctor unit or a clinic visit be ckney, RN cancer pat wit ress with , , BS, MAS our ients the pain measu are asked to comple h experienci pai rement too te ng and imp n they are of whether l that provid a to relieve lement wa the it. Pain ys gree. Patien y are presently in es some expression pai physical end time, psycholog steals away social what to circ ts have trouble, how n, and to what deica le tually absent urance and can ma l well-being, and pain was bad (a happy face or a ever, interpreting ke quality ver of life virand adequa for some patients. cause they in the morning but y sad face) if their Ac te cur treatment too not so bad ment nee for effectiv ate assessment doctor. Fur k a pain pill before now bed to be pri e pain ma thermore, orities for the cancer is this info coming to see the viewed by all of us wo nagefield. any rma rking in I feel confide and sometim one during their visi tion actually rent you wil t? Sometim es provoking l find these es it is, Certainly it is not. and articles tho con taining val will assist ught cer patien one of the greatest fea uab you le info in ts is the fea reassessing rma rs well as dev r of pain and expressed by canyour curren tion that elo pin g more effe t patients suffering and future patien as ctive the fectively ma ts have quality of life ways to help your naged. Q by having pain efÂŠ 2013 Gre en Hill Hea lthcare Com munication s, LLC

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biotheranostics.com REFERENCE: Kim B, Schroeder BE, Schnabel CA, et al. Physician-Reported Clinical Utility of the 92-Gene Molecular Classifier in Tumors With Uncertain Diagnosis Following Standard Clinicopathologic Evaluation. Personalized Medicine in Oncology. 2013;2:68-76. CancerTYPE ID Indications for Use and Limitations CancerTYPE ID is indicated for use in tumor specimens from patients diagnosed with malignant disease and is intended to aid in the classification of the tissue of origin and tumor subtype in conjunction with standard clinical and pathological assessment by a qualified physician. CancerTYPE ID is not intended to predict patient survival benefit, treatment efficacy or to distinguish between benign versus malignant lesions. Tumor types not included in the CancerTYPE ID reference database may exhibit RNA expression patterns that are similar to RNA expression patterns within the reference database. This test was developed and performance characteristics have been determined by bioTheranostics, Inc. It has not been cleared or approved by the U.S. Food and Drug Administration. This test is used for clinical purposes. It should not be regarded as investigational or for research. How this information is used to guide patient care is the responsibility of the physician. bioTheranostics is certified under the Clinical Laboratory Improvement Amendments of 1988 as qualified to perform high complexity clinical laboratory testing. CancerTYPE ID is a registered trademark of bioTheranostics, Inc. © 2013 bioTheranostics, Inc.

CTX-221 04/13

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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