H. Kluger, M. Sznol, M. Callahan, M. Postow et al.

Survival, 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): 



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.


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.


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%).


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.