Combined Inhibition of PD-L1, MEK, and BRAF Active in Advanced Melanoma CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* May 29 - June 2, 2015 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene Corporation, Genentech, Incyte, and Novartis.

Targeted Inhibition in Current Melanoma Treatment BRAF inhibitor (eg, dabrafenib) ± MEK inhibitor (eg, trametinib) results in clinically significant responses in BRAFV600-mutant melanoma, but durability transient Immunotherapy responses in melanoma more durable BRAF/MEK inhibition modifies tumor-immune response interaction Hypothesis: combining anti–PD-L1 immunotherapy with BRAF and MEK inhibitors may increase frequency of durable responses in advanced BRAF-mutant melanoma Current multicenter, open-label, phase I study evaluated combining MEDI4736 (anti–PD-L1 antibody) with trametinib ± dabrafenib in advanced melanoma Ribas A, et al. ASCO 2015. Abstract 3003.

Combined PD-L1, MEK, BRAF Inhibition in Advanced Melanoma: Study Design Phase I study: 3 pt cohorts and regimens evaluated All pts had stage IIIC/IV melanoma and ECOG PS 0-1 Prior immunotherapy permitted, but not BRAF or MEK inhibitors BRAF V600E/K mutation–positive pts M + T + D MEDI4736 3 or 10 mg/kg q2w for 12 mos + Trametinib 2 mg QD + Dabrafenib 150 mg BID, both until PD (n = 26) M + T MEDI4736 10 mg/kg q2w for 12 mos + Trametinib 2 mg QD until PD (n = 20) BRAF wild-type pts BID, twice daily; D, dabrafenib; ECOG PS, Eastern Cooperative Oncology Group performance status; M, MEDI4736; PD, progressive disease; q2w, every 2 weeks; QD, once daily; T, trametinib. T  M Trametinib 2 mg QD for 6 wks, with MEDI4736 10 mg/kg q2w started at Wk 4 for 12 mos (n = 19) BRAF wild-type pts Ribas A, et al. ASCO 2015. Abstract 3003.

Combined PD-L1, MEK, BRAF Inhibition in Adv Melanoma: Baseline Characteristics M + T + D (n = 26) M + T (n = 20) T → M (n = 19) Mean age, yrs (range) 47.2 (23-71) 62.2 (31-85) 58.7 (34-84) Male, % 54 65 53 ECOG PS 0, % 73 NA Mutation status, % BRAF WT BRAF V600E BRAF V600E/K NRAS 27 100 15 32 Stage IV disease, % 81 90 79 Prior systemic treatment, % Median regimens (range) 38 0 (0-2) 60 2 (0-4) 74 1 (0-4) Any prior immunotherapy, % Anti–CTLA-4 Anti–PD-1 Cytokine-based therapy 23 55 30 35 42 26 D, dabrafenib; ECOG PS, Eastern Cooperative Oncology Group performance status; M, MEDI4736; NA, not assessed; T, trametinib. Ribas A, et al. ASCO 2015. Abstract 3003. Reprinted with permission.

Combined PD-L1, MEK, BRAF Inhibition in Adv Melanoma: Overall Safety Treatment-Related Safety Outcome, % M + T + D (n = 26) M + T (n = 20) T → M (n = 19) Any AE 100 95 Grade ≥ 3 AE 46 45 47 Serious AE 31 20 21 AE leading to discontinuation of any drug 12 15 AE leading to death AE related to MEDI4736 54 35 42 AE related to trametinib and/or dabrafenib 85 79 AE, adverse event; D, dabrafenib; DLTs, dose-limiting toxicities; M, MEDI4736; T, trametinib. DLTs observed in 2 pts Reversible grade 3 thrombocytopenia in M + T + D cohort Reversible grade 3 choroidal effusion in M + T cohort Ribas A, et al. ASCO 2015. Abstract 3003. Reprinted with permission.

Combined PD-L1, MEK, BRAF Inhibition in Adv Melanoma: Treatment-Related AEs M + T + D (n = 26) M + T (n = 20) T → M (n = 19) All Gr Gr ≥ 3 Diarrhea 39 4 50 32 5 Fatigue 58 30 26 Pyrexia 77 10 11 Rash 31 35 47 Chills 54 Vomiting 42 Arthralgia Nausea 21 Peripheral edema 19 15 AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; D, dabrafenib; DLTs, dose-limiting toxicities; Gr, grade; M, MEDI4736; T, trametinib. ALT/AST increases (19%, mostly < grade 3) also observed with M + T + D No severe hypertension observed in M + T + D cohort Ribas A, et al. ASCO 2015. Abstract 3003. Reprinted with permission.

Combined PD-L1, MEK, BRAF Inhibition in Advanced Melanoma: Response Efficacy Outcome M + T + D (n = 26) M + T (n = 19) T → M (n = 15) ORR, % 69 21 13* DCR, % 100 79 80 SD ≥ 12 wks, % 15 53 40 Ongoing responders, % 89 50 Range of ongoing response duration, wks 7.7+ to 50.6+ 7.9+ to 24.7+ 7.0+ *Median follow-up of 2.7 mos. 5 additional pts with ongoing unconfirmed PR. D, dabrafenib; DCR, disease control rate; M, MEDI4736; ORR, overall response rate; PR, partial response; SD, stable disease; T, trametinib. Evidence of immune activation posttreatment observed in all cohorts Included increases in tumor-infiltrating CD8+ cells and increased plasma levels of interferon gamma and other Th1-associated factors Strongest and most consistent immune activation response observed with M + T + D vs M + T or T → M cohorts Ribas A, et al. ASCO 2015. Abstract 3003. Reprinted with permission.

Combined PD-L1, MEK, BRAF Inhibition in Advanced Melanoma: Conclusions Combination treatment with PD-L1 inhibitor, MEK inhibitor, and BRAF inhibitor feasible and tolerable No MTD identified; full doses of all agents selected for dose expansion Toxicity profiles of combinations consistent with single-agent toxicity profiles No apparent exacerbation of immune-related AEs Patients with BRAF-mutant melanoma treated with MEDI4736 + trametinib + dabrafenib showed greatest immune activation and achieved highest response rates Majority of pts have ongoing responses Markers of immune activation observed in all cohorts following treatment initiation AEs, adverse events; MTD, maximum tolerated dose. Ribas A, et al. ASCO 2015. Abstract 3003.

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