1085OSURVIVAL, RESPONSE DURATION, AND ACTIVITY BY BRAF MUTATION (MT) STATUS IN A PHASE 1 TRIAL OF NIVOLUMAB (ANTI-PD-1, BMS-936558, ONO-4538) AND IPILIMUMAB (IPI) CONCURRENT THERAPY IN ADVANCED MELANOMA (MEL).

ABSTRACT Aim: In a phase 1 trial, concurrent therapy with nivolumab (N) + IPI (N + I) led to an objective response rate (ORR) of 40% and evidence of clinical activity in a further 25% of patients (pts). Tumor regression was generally rapid, with >80% reduction in tumor measurements in 31% of pts. We report updated survival, efficacy and clinical activity by BRAF MT status across all pt cohorts. Methods: MEL pts (≤3 prior therapies) received concurrent N + I IV Q3W × 4 doses (Table; n = 53) followed by N Q3W × 4 doses. At wk 24, pts without progression by immune-related criteria (iRC) and no dose limiting toxicities could continue N + I Q12W × 8 doses. An additional 41 pts (cohort 8, last pt enrolled Nov 2013) were treated with N + I 1 + 3 mg/kg Q3W × 4 doses, followed by N 3 mg/kg Q2W (selected regimen for phase 2/3 trials). Tumor responses were evaluated by WHO and iRC. Results: Of the total 94 pts, 53% were stage M1c; 45% had prior systemic therapy. In the initially enrolled cohorts, ORR was 42% (22/53); median duration of response (DOR) not reached (NR); 9/53 (17%) demonstrated confirmed complete response. Fourteen of 22 pts (64%) with an OR had DOR ≥24 wks (range 24.7 + , 105.7+). Clinical activity was similar irrespective of BRAF MT status. Tumor reduction of ≥80% by wk 36 was observed in 22/53 pts (42%). One- and 2-yr OS rates were 85% and 79%, respectively. In cohort 8, ORR was 43% (17/40). For aggregate safety across cohorts, grade 3–4 treatment-related AEs occurred in 58/94 pts (62%); most common: increased lipase (15%), ALT (12%) and AST (11%). Conclusions: Concurrent N + I demonstrated encouraging survival and a manageable safety profile using standard safety algorithms in advanced MEL pts. Responses were observed regardless of BRAF MT status and were durable in many pts. The preliminary analysis of cohort 8 confirms the activity of N + I observed in the initially enrolled concurrent cohorts. Nivolumab (mg/kg) + IPI (mg/kg) [n] 1-yr OS rate, % [pts at risk] Median OS, mo ACAR, % ACAR by BRAF MT status,* % [n] Initially enrolled concurrent cohorts [53] 85 [44] 39.7 70 60 [10] 73 [26] 71 [17] 0.3 + 3 [14] 57 [8] 27.2 57 50 [4] 67 [3] 57 [7] 1 + 3 [17] 94 [15] NR 65 50 [2] 50 [6] 78 [9] 3 + 1 [16] 94 [15] NR 81 67 [3] 85 [13] – [0] 3 + 3 [6] 100 [6] NR 83 100 [1] 75 [4] 100 [1] Cohort 8 [41] Insufficient follow-up NR 48 58 [7] 46 [12] 100 [2] n: no. response-evaluable pts. ACAR: aggregate clinical activity rate = CR + PR + uCR + uPR + irCR + irPR + SD ≥ 24 wk+ irSD ≥24 wk. *Retrospective analysis. Disclosure: M. Sznol: Paid consultant and scientific advisory board-Bristol-Myers Squibb, Genentech/Roche, MedImunne, Amgen, Nektar, Symphogen, Merus, Amphivena, NeoStem, Anaeropharma, BeiGene, Kyowa-Kirin, Immune Design, Lion Biotechnologies, Seattle Genetics; M. Postow: BMS-consultant advisor, research funding; R. Gordon: BMS remuneration; N.H. Segal: Ad Board-MedImmune, Alkermes Scientific, Imugene; Research Funding BMS, MedImmune, Pfizer; N. Rizvi: Consultant Advisor-BMS; Honoraria-BMS, Medimmune, Genentech/Roche; A. Lesokhin: Consultant/advisor to BMS; Research Funding BMS; M.B. Atkins: Consultant advisor, honoraria- BMS; J. Kirkwood: Consultant advisor-BMS, Merck, GSK, Celgene, Vical, Ziopharm; Research Funding Prometheus; W. Feely: BMS-employee, stock; Q. Hong: BMS-employee, stock; S. Krishnan: BMS-employee, stock; J. Wolchok: Consultant/advisor to BMS; Research Funding BMS. All other authors have declared no conflicts of interest.