Updates in Metastatic Melanoma

SCSHP 214 Annual Meeting Updates in Metastatic Melanoma LeAnn B. orris, PharmD, BCPS, BCOP Assistant Professor South Carolina College of Pharmacy Background Estimated 76,69 new cases in 213 Increasing in men more rapidly than any other malignancy 9,48 deaths due to melanoma Males: 6,28 Females: 3,2 age at presentation: 59 Ranks second in terms of loss of years of potential life Jamal A, et al. CA Cancer J Clin. 213; 63: 11-3. CC. Clinical Practice Guidelines Melanoma v3.214. Available at: www.nccn.org. Accessed on 2/14/13. Disclosure I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation History of Melanoma Treatment Immune component to spontaneous regressions in melanoma IL-2 approved as cancer immunotherapy 197 198 199 2 21 IF-α approved as cancer immunotherapy Use of dacarbazine and temozolomide in melanoma Kirkwood J. J Clin Oncol. 26:3445-55. Objectives Treatment by Stage Evaluate current guidelines and recommendations for the treatment of metastatic melanoma Compare and contrast the role of various agents including chemotherapy and immunologics Analyze recent clinical trials for newly developed therapies Stage IV LDH and encourage CT, MRI, and PET Limited (Resectable) Disseminated (Unresectable) Resect Observation o Brain Metastases Brain Metastases Clinical Trial Observation Systemic Therapy or Clinical Trial Palliative radiation Best Supportive Care CC. Clinical Practice Guidelines Melanoma v3.214. Available at: www.nccn.org. Accessed on 2/14/14. 1

Systemic Therapy Options Preferred Regimens Ipilimumab (Category 1) (Category 1) Dabrafenib (Category 1) Dabrafenib + Trametinib Clinical Trial High dose IL-2 Other Active Regimens Trametinib (Category 1) Imatinib for c-kit tumors Dacarbazine Temozolomide Albumin-bound paclitaxel Dacarbazine or temozolomide based combination therapy/biochemotherapy Paclitaxel (Category 2B) Paclitaxel/carboplatin (Category 2B) High-Dose Interleukin-2 and Taxanes Interleukin-2 rates: 15% 25% Complete response: 2% 5% of patients FDA-approved dose: 6, IU/kg dose q8h x 14 doses Multiple toxicities affecting several organs requiring attentive management of symptoms and well-trained staff Administration in critical care unit Capillary Leak syndrome Taxanes Paclitaxel single agent: response rates: 6% 18% Combination therapy o increase in response or survival vs paclitaxel Increase in toxicity as compared with single-agent therapy CC. Clinical Practice Guidelines Melanoma v3.214. Available at: www.nccn.org. Accessed on 2/14/14. Atkns MB, et al. J Clin Oncol. 1999;17:215-16. Dacarbazine Metastatic Melanoma Dose: - 25 mg/m 2 /day IV x 5 days q 21 days - 85-1 mg/m 2 IV q 21 days Rate: 1% 2% 5-year survival rate: <2% Can be used in combination Lens MB. Expert Opin Pharmcother. 23;4(12):225-11. Buzzaid et al DTIC CVD Chapman et al DTIC CBDT 45 46 118 18 (CR + PR) 11% 24% 1.2% 18.5% Survival 5.3 6.6 6.3 7.7 DTIC = dacarbazine; CVD = cisplatin, vinblastine, and dacarbazine; CBDT = cisplatin, bischloroethylnitrosourea, dacarbazine, and tamoxifen; CR = complete response; PR = partial response Biochemotherapy Combination of chemotherapy and biological agents Dacarbazine based regimen ± Interferon alfa (IF- ) Interferon alfa (IF- ) + Interleukin-2 (IL-2) Three modes of administration Sequential Outpatient Sequential little to no benefit Concurrent Toxicity more with biochemotherapy Myelosuppression Constitutional symptoms Hemodynamic changes CC. Clinical Practice Guidelines Melanoma v4.211. Available at: www.nccn.org. Accessed on 6/28/11. Temozolomide Metastatic Melanoma Dose: 15 2 mg/m 2 /day x 5 days q 28 days Increased median PFS with temozolomide Trend toward increase in overall survival with temozolomide Increased health-related quality of life Maintenance of physical functioning at week 12 Middleton et al DTIC Temozolomide Middleton MR, et al. J Clin Oncol. 2;18:158-66. 149 156 DTIC = dacarbazine; PFS = progression-free survival PFS (P =.1) 1.5 1.9 Survival (P =.2) 6.4 7.7 Biochemotherapy Regimen Sequential (Eton et. al) Cisplatin 2 mg/m 2 /day D1-4, 22-25 Vinblastine 1.5 mg/m 2 D1-4, 22-25 Dacarbazine 8 mg/m 2 D1 and 22 IL-2 9 million IU/m 2 CI D5-8, 17-2,26-29 IF- 5 MU/m 2 /day SQ D5-9,17-21,26-3 Concurrent (Atkins et. al) Cisplatin 2 mg/m 2 /day D1-4 Vinblastine 1.2 mg/m 2 D1-4 Dacarbazine 8 mg/m 2 D1 only IL-2 9 million IU/m 2 CI D1-4 IF- 5 MU/m 2 /day SQ D1-5,8,1,12 GCSF 5 mcg/kg SQ daily on D7-16 Eton et al. J Clin Oncol 16: 1752-1759. Atkinas et al. J Clin Oncol 26: 5748-5754 Rate (%) 48% vs. 25% (p =.1) 19.5% vs. 13.8% (p =.141) OS 11.9 vs. 9.2 (p =.6) 9 vs. 8.7 (p =.639) OS= Overall Survival, IL-2 = Interleukin-2, IF-a=Interferon alpha, GCSF = filgrastim 2

Commonly Used Regimens T-Cell Activation and Ipilimumab Therapy Rate Availability Toxicity Overall Survival Dacarbazine ~1% High Low 6 7 o treatment Temozolomide proven to HD IL 2 16% Low High 11.4 improve OS in Combination ~2% High Moderate 6 7randomized Chemotherapy phase III Biochemotherapy 2% High High 9 trials Signal 2 Signal 1 Antigen Presenting Cell B7 B7 MHC-Ag CD28 CTLA 4 Ipilimumab TCR T Cell Middleton MR, et al. J Clin Oncol. 2;18(1):158-66; Atkins MB et al. J Clin Oncol. 1999;17(7):215-16. Atkins MB et al. J Clin Oncol. 28;26(35):5748-54; Chapman PB et al. J Clin Oncol. 1999;17(9):2745-51. Egen JG, et al. at Immunol. 22;3(7):611-8. History of Melanoma Treatment Immune component to spontaneous regressions in melanoma IL-2 approved as cancer immunotherapy 197 198 199 2 211 Anti-CTLA 4 indication Targeting the CTLA-4 Receptor Two fully human anti CTLA-4 monoclonal antibodies Ipilimumab (an IgG1 isotype) Tremelimumab (an IgG2 isotype) Both studied as single agents and in combination with chemotherapy IF-α approved as cancer immunotherapy Use of dacarbazine and temozolomide in melanoma Both have demonstrated the ability to induce tumor regression and may prolong time to disease progression Tremelimumab failed to show overall survival benefit as first line therapy Kirkwood J. J Clin Oncol. 26:3445-55. Weber J. Oncologist. 28;13(suppl 4):16-25. Ribas A. ASCO Annual Meeting, May 3-June 3, 28;Chicago, IL. Abstr LBA911. T-Cell Activation and Ipilimumab Immune-Related Adverse Events (IRAEs) Signal 2 Signal 1 Antigen Presenting Cell B7 B7 MHC-Ag CD28 CTLA 4 TCR T Cell Effects are a result of tissue damage associated with inflammatory T-cell infiltrates involving the skin and gastrointestinal tract Mild and self-limiting The most commonly documented IRAEs: Rash Colitis Hepatitis Hypophysitis (rare, but least reversible) Egen JG, et al. at Immunol. 22;3(7):611-8. Peggs KS. Curr Opin Immunol. 26;18:26-13. 3

Immune-Related Adverse Events (IRAEs) Severe effects occur infrequently, but can be life threatening Onset of IRAEs Extremely variable Ranges from days to weeks Management Antimotility agents initiated on day 1 Steroids should be initiated if symptoms unresolved Monitoring Liver function tests (LFTs) at baseline and periodically after initiation of anti-ctla 4 agents Peggs KS. Curr Opin Immunol. 26;18:26-13. Ipilimumab in Previously TREATED Metastatic Melanoma (2) Ipi +gp1: 1 months HR:.68 p <.1 Ipi: 1.1 months HR:.66 p =.3 gp1: 6.4 months Hodi FS, et al. ew Engl J Med. 21;363(8):711-23. Ipi +gp1: 2.76 months Ipi: 2.86 months gp1: 2.76 months Ipi = Ipilimumab % Correlation of to IRAEs Ipilimumab in Previously TREATED Metastatic Melanoma (2) Re-induction available if patient progressed 31 patients underwent re-induction 12/23 had stable disease (Ipi + gp1 arm) Adverse Events IRAEs 6% vs. 3% (gp1) Most common Diarrhea: 27 31% (any grade) Corticosteroids Infliximab (4 patients) Deaths 7/14 were IRAE related *IRAEs or 4 only **IRAE onset is variable Weber J. Oncologist. 27; 12:864-72. Hodi FS, et al. ew Engl J Med. 21;363(8):711-23. Ipilimumab in Previously TREATED Metastatic Melanoma (2) Primary endpoint: Overall Survival Secondary endpoints: overall survival in ipilimumab vs. gp1, best overall response rate, duration of response, and progression free survival Inclusion Criteria: Unresectable Stage III or IV Previously treated Age at least 18 y/o Life expectancy of 4 months + HLA-A*21 ECOG or 1 Exclusion Criteria: Other Cancer diagnosis Previous Anti-CTLA4 therapy or cancer vaccine Inflammatory Bowel Disease Autoimmune disease Untreated CS metastases Chronic use of corticosteroids Hodi FS, et al. ew Engl J Med. 21;363(8):711-23. RADOMIZATIO (3:1:1) Arm 1 (n=43) Induction Ipilimumab 3mg/kg + gp1 Q 3W x 4 Arm 2 (n=137) Ipilimumab + gp1 placebo Q3W x 4 Arm 3 (n=136) Ipilimumab placebo + gp1 Q3W x 4 BRAF Mutations in Melanoma Davies MA, et al. Surg Oncol Clin Am. 211;2(1):165-8. BRAF Mutations ~5% of melanoma BRAF V6E Most frequent BRAF mutation Constitutive active kinase Kinase activity increased 5-times 4

Mitogen-Activated Kinase Signaling (MAPK) UTREATED Metastatic Melanoma RAS BRAF V6E MEK Dabrafenib RAS BRAF V6E MEK ERK ERK Proliferation and Survival Ribas A, et al. at Rev Clin Oncol. 211;8(7):426-33. Apoptosis Overall Survival: 84% vs. 64 % ( vs Dacarbazine) Rates: 48% vs. 5% (crossover was allowed) Progression Free Survival: 5.3 vs. 1.6 months Robert et al. Engl J Med June 211; 364: 2517-26. UTREATED Metastatic Melanoma Primary endpoint: Overall Survival and Progression Free Survival Secondary endpoints: rate, response duration, and safety Inclusion Criteria: Unresectable Stage III or IV Previously UTREATED + BRAF V6E mutation Age at least 18 y/o Life expectancy of 3 months ECOG or 1 Adequate labs Exclusion Criteria: History of cancer in 5 years CS metastases Concomitant anticancer treatment RADOMIZATIO (1:1) Arm 1 (n=337) 96 mg twice daily Arm 2 (n=338) Dacarbazine 1mg/m 2 every 3 weeks UTREATED Metastatic Melanoma Adverse Events # of patients (%) Arthralgias Grade 2 Rash Grade 2 Fatigue Grade 2 Cutaneous squamous cell Keratoacanthoma Grade 2 ( = 336) 6 (18) 11 (3) 33 (1) 28 (8) 38 (11) 6 (2) 4 (12) 7 (2) 2 (6) Dacarbazine ( = 282) 1 (< 1) 2 (< 1) 33 (12) 5(2) 1 (<1) Chapman PB et al. Engl J Med 211; 64: 257-16. Robert et al. Engl J Med June 211; 364: 2517-26. UTREATED Metastatic Melanoma ( = 337) Dacarbazine ( = 338) Mean Age - yr 56 (21-86) 52 (17-86) Male sex - no 2 (59) 181 (54) ECOG Performance Status O 1 Metastasis Stage M1a M1b M1c Lactate Dehydrogenase UL > UL 229 (68) 18 (32) 34 (1) 62 (18) 221 (66) 142 (42) 195 (58) 23 (68) 18 (32) 4 (12) 65 (19) 22 (68) 142 (42) 196 (58) UTREATED Metastatic Melanoma improved overall survival and progression free survival in comparison to dacarbazine in patients with BRAF V6E mutation Adverse effects are minimal Cutaneous squamous cell Keratoacanthomas FDA approval in 211 Wild-type BRAF Robert et al. Engl J Med June 211; 364: 2517-26. Robert et al. Engl J Med June 211; 364: 2517-26. 5

Dabrafenib: Clinical Evidence R A IIIc or IV Melanoma D BRAF V6E positive O o prior therapy except IL2 Treated brain mets M I ( = 25) Z E BREAK-3 Study 3:1 Dabrafenib (B) 15mg PO BID Dacarbazine (D) 1 g/m 2 IV Q 3 weeks Allow cross-over upon progression Primary Progression-free survival Secondary Overall survival duration Safety Trametinib: Clinical Evidence R A IIIc or IV Melanoma BRAF V6E/K positive D One prior chemotherapy O exclude BRAFi, MEKi, and ipilimumab M Treated brain mets I ( = 322) Z E METRIC Study 2:1 Trametinib 2 mg PO Daily Dacarbazine 1 gram/m2 IV q3w or Paclitaxel 175mg/m2 IV q3w Allow cross-over upon progression Primary Progressionfree survival Secondary Overall survival duration Safety Hauschild A, et al. Lancet. 212;38(9839):358-65. IL2: Interleukin 2 Flaherty KT, et al. ew Engl J Med. 212;367(2):17-14. BRAFi: BRAF inhibitor; MEKi: MEK inhibitor Dabrafenib: Clinical Evidence Trametinib: Clinical Evidence Change at maximum reduction from baseline measurement (%) ORR = 5% (3% CR) PFS = 5.1 mo. Maximum per cent change in baseline target lesions HR Death:.54 (95% CI:.32-.92); P =.1 HR Progression:.45 (95% CI:.33-.63); P <.1 ORR: 22% (2% CR) Months since Randomization Kaplan-Meier Curve for Overall Survival Hauschild A, et al. Lancet. 212;38(9839):358-65. Courtesy of Kevin B. Kim, MD Flaherty KT, et al. ew Engl J Med. 212;367(2):17-14. HR: Hazard ratio; ORR: Overall response rate Dabrafenib: Clinical Evidence MAPK Inhibitors--Clinical Features Rapid onset of response Short duration of benefit BRAF inhibitors: Paradoxical MAPK activation in select tissues Do not use in patients with mutant RAS or wild-type BRAF melanoma Cutaneous squamo-proliferative lesions Concern about other secondary malignancies Months Kaplan-Meier Curve for Progression-Free Survival Hauschild A, et al. Lancet. 212;38(9839):358-65. MEK inhibitor: Place in therapy: BRAF inhibitor intolerance o issue with paradoxical MAPK activation 6

Treatment Decisions Which agent is first line? Ipilimumab vs BRAF Quick response vs. durable benefit? Which BRAF is preferred? Dabrefenib When do you use single agent Tremitinib? When do you use combination therapy? Dabrafenib + Tremitinib Rapid Progression at BRAFi Discontinuation Retrospective analysis 29-212: Vem as part of clinical trial OS to BRAFi (%) to Ipi IT BRAFi 16 31.2 75 /A BRAFi IT 1 /A 52 (all ipi) ALL 1 had PD at 6 months PFS.7m; OS 2.2m 5% of vem patients had Rapid PD ( OS 4 months) Ackerman A, et al. J Clin Oncol. 212;3:abstr 8569. Durability of Let s evaluate the numbers Ipi-Patients out 7+ years 2% Ipi 3mg/kg Q3 weeks X 4 Vem 96mg BID Dacabazine 1mg/m2 Q3 weeks rate (%) Overall Survival Progression Free Survival 12- month overall survival (%) 137 1.1 1.9 2.8 45.6% 337 48.4 13.6 5.3 56% 338 5.4 9.7 1.6 44% Dab 15mg 187 5% R 5.1 R Ipi Ipilimumab Vem-; Dab- Dabrafenib; R ot reached Prieto PA, et al. Clin Cancer Res. 212;18:239-47 Chapman PB, et al. Engl J Med. 211;364:257 16. Hodi FS, et al. Engl J Med. 21;363:711-23 Hauschild A, et al. Lancet. 212;38(9839):358-65. Durability of : How fast and who? Real Trial Data Chapman PB, et al. Engl J Med. 211;364:257-16. Other standard therapies Plateau in the Curve? Hypothetical Trial Data BRAF Inhibitors (BRAFi s) onset of response - QUICK!!! 2.7 months Dabrafenib 6.3 weeks Patients with BRAF mutation ** Subgroup analyses: Hazard Ratios (95% CI) BRAFi s reduce risk of death in M1c patients Ipilimumab M, M1a, M1b S.47 M1c.32.72 Chapman PB, et al. Engl J Med. 211;364:257 16. Hodi FS, et al. Engl J Med. 21;363:711-23 S: ot significant 7

Adverse Drug Events Dabrafenib 5% of patients experienced ADE 18% of patients experienced; removed by simple excision BRAFi s Ipilimumab 6% of patients experienced ADE with mean time to resolution at 6.3 weeks 7 deaths ADE: adverse drug event SCC/KA: squamous cell carcinoma or keratoacanthoma Chapman PB, et al. Engl J Med. 211;364:257 16. Hodi FS, et al. Engl J Med. 21;363:711-23 Potential Disadvantages eeds to be taken WITHOUT food Drugs that increase gastric ph (ie PPI s and H2 blockers) may decrease concentrations Glucose-6-phosphate dehydrogenase deficiency (G6PD) Different toxicity profile Hyperglycemia (all grades-5%; grade 3/4-6%) Diabetics Drug Interactions Inducer of CYP3A4 (moderate in-vivo) Tafinlar (dabrafenib) package insert. Research Triangle Park, C: GlaxoSmithKline USA, May 213. Individualizing Therapies Rapidly Growing or Symptomatic BRAF Inhibitor BRAFi Intolerance YES BRAF Mutation Slow Growing and Asymptomatic Immunotherapy O Rapidly Growing or Symptomatic Chemotherapy or Biochemotherapy? 96mg BID with or without food Disadvantages in this patient o validated data in patients with brain metastases Several published cases and case-series Side effect profile QTc of 5 ms or greater must be witheld Hepatoxicity monitor LFTs and bilirubin ew non-cutanous squamous cell carcinoma Photosensitivty Opthalmic reactions Drug-drug interactions Avoid with CYP 3A4 MEK Inhibitor BRAFi: BRAF inhibitor Zelboraf(vemurafenib) package insert. San Francisco CA: Genentech, July213. Dabrafenib Single Agent Trametinib Potential Advantages o EKG s necessary Higher brain concentrations compared to vemurafenib? Different toxicity profile Pyrexia (all grade-28%; serious-3.7%) Lack of photosensitivity Lack of hepatotoxicity? Less arthralgias? (all grade-27%; grade 3/4-1%) SCC/KA s still a concern (7%) Tafinlar (dabrafenib) package insert. Research Triangle Park, C: GlaxoSmithKline USA, May 213. Mittapalli RK, et al. J Pharmacol Exp Ther. 213;344:655-64. Long GV, Margolin KA. Am Soc Clin Oncol Educ Book. 213;213;393-8. MEK inhibitor for V6E or V6K o data in brain metastases patients Dose: 2mg daily one hour before or 2 hours after a meal Side effect profile Cardiomyopathy monitoring 1 month after initiation, then every 2-3 months thereafter (occurred in 11%) Ocular Retinal epithelial detachments.8% Retinal vein occlusion.2% Pulmonary Pneumonitis 1.8% Mekinist (trametinib) package insert. Research Triangle Park, C: GlaxoSmithKline USA, May 213. 8

Maximum percent change in baseline target lesions 8 6 4 2 2 4 6 8 1 Trametinib Post BRAFi Failure 266% 155% 1 * Kim KB, et al. J Clin Oncol. 213;31 (4):482-9. K K V6K * BRAF inhibitor intolerance M1a M1b M1c = 4 ORR: % K K Trametinib should be reserved for patients who are intolerant to BRAFi, not those who are resistant. K * * Dabrafenib and Trametinib: Side effect profile Side effect profile in combination therapy Acneiform dermatitis (8% in trametinib with no /4 in combination) Proliferative skin lesions (7% in combination vs 17% in single agent therapy) *More pyrexia, cardiovascular issues, neutropenia, fatigue, alopecia, and ocular effects in COMBO therapy o Overall Survival Data Flaherty KT, et al. ew Engl J Med. 212;367(2):17-14. Included: BRAF V6E or V6 K Patients with brain metastases with stable disease were allowed to enroll At least 18 years of age ECOG of or 1 Excluded: Untreated brain metastases Risk of cardiovascular disease or interstitial lung disease Risk of retinal vein occlusion and central serous retinopathy Dabrafenib and Trametinib: Clinical Evidence R A D O M I Z E Part C of Phase I and II study Primary Dabrafenib 15mg BID Incidence of cutaneous squamous-cell carcinoma Progression free Dabrafenib 15mg BID survival Trametinib 1mg daily Dabrafenib 15mg BID Trametinib 2mg daily Secondary Overall survival Pharmacokinetic activity Conclusions Pharmacologic options expanding for metastatic melanoma Treatment options should be individualized based on Mutation analysis Disease tempo Performance status Co-morbidities Subtle differences between vemurafenib and dabrafenib MEKi: BRAFi intolerance, not resistance Additional research needed to determine appropriate sequencing and overall survival benefit Flaherty KT, et al. ew Engl J Med. 212;367(2):17-14. BRAFi: BRAF inhibitor Dabrafenib and Trametinib: Clinical Evidence Dabrafenib Dabrafenib 15/1 Dabrafenib 15/2 Patients = 54 =54 =54 Progression Free Survival Progression Free Survival at 12 mo Complete or Partial response (# of patients) Duration of Flaherty KT, et al. ew Engl J Med. 212;367(2):17-14. 5.8 9.2 (HR.56) 9.4 (HR.39) 9 26 41 29 27 (S) 41 (p.3) 5.6 9.5 1.5 15/1 Trametinib 1mg 15/2 Trametinib 2mg S: ot significant SCSHP 214 Annual Meeting Updates in Metastatic Melanoma LeAnn B. orris, PharmD, BCPS, BCOP Assistant Professor South Carolina College of Pharmacy 9