Abstract CT002: Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma (MEL)
Authors: Postow Michael , Chesney Jason , Pavlick Anna , Robert Caroline , Grossmann Kenneth , McDermott David , Linette Gerald , Meyer Nicolas , Giguere Jeffrey , Agarwala Sanjiv , Shaheen Montaser , Ernstoff Marc , Minor David , Salama April , Taylor Matthew , Ott Patrick , Jiang Joel , Horak Christine , Gagnier Paul , Wolchok Jedd , Hodi F. Stephen 
Published: July 2016

Abstract
Background: This phase II trial (CheckMate 069) demonstrated a statistically significant improvement in objective response rate (ORR) and progression-free survival (PFS) with the combination of NIVO+IPI vs. IPI alone in treatment-naïve patients (pts) with BRAF wild-type MEL (Postow et al. N Engl J Med 2015;372:2006). ORR was 61% for NIVO+IPI vs 11% for IPI alone (P&lt;0.0001). Here, we report updated efficacy data and the first overall survival (OS) results from this study.
Methods: Pts (N = 142) were randomized 2:1 (with stratification by BRAF mutation status) to receive either NIVO 1 mg/kg + IPI 3 mg/kg or IPI 3 mg/kg + placebo every 3 weeks x 4 doses, followed by NIVO 3 mg/kg or placebo, respectively, every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed ORR in pts with BRAF wild-type tumors. Secondary endpoints included PFS in pts with BRAF wild-type tumors, ORR in pts with BRAF V600 mutation-positive tumors, and safety. OS was an exploratory endpoint. The most recent database lock occurred in August of 2015, representing a minimum follow-up of 18 months.
Results: In the current analysis, median PFS in BRAF wild-type pts had not yet been reached with the NIVO+IPI combination and was 4.3 months for IPI alone (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.20-0.57; P&lt;0.0001). The 12- and 18-month PFS rates were, respectively, 55.1% and 53.4% for NIVO+IPI vs. 16.2% and 8.1% for IPI alone. At 18 months of follow-up, OS rates in BRAF wild-type pts were 73% for NIVO+IPI vs. 56% for IPI alone, and median OS had not been reached in either group (HR: 0.56; 95% CI: 0.29-1.10; P = 0.089). While 26 of 46 pts (57%) randomized to the IPI group had crossed over to receive NIVO alone upon disease progression, sensitivity analyses showed similar OS results when these pts were censored. In all randomized pts, median change from baseline in target lesions was a 70% reduction for NIVO+IPI vs. a 5% increase for IPI alone. Median duration of response was not reached in either group. Grade 3-4 treatment-related adverse events were reported more frequently with NIVO+IPI (55%) than with IPI alone (22%), and led to discontinuation in 30% and 9% of pts, respectively. Treatment-related select AEs in the combination arm were consistent with the initial report and most resolved with immune-modulating medications (&gt;85% across organ categories).
Conclusions: In this updated analysis, NIVO+IPI continued to show improved PFS vs. IPI alone, with an apparent plateau after 12 months in the combination group. At 18 months of follow-up, there was a trend toward higher OS rates in pts who received combination therapy. Further efficacy updates, including 2-year OS rates, will be presented according to BRAF mutation status and for all randomized pts.
Citation Format: Michael Postow, Jason Chesney, Anna Pavlick, Caroline Robert, Kenneth Grossmann, David McDermott, Gerald Linette, Nicolas Meyer, Jeffrey Giguere, Sanjiv Agarwala, Montaser Shaheen, Marc Ernstoff, David Minor, April Salama, Matthew Taylor, Patrick Ott, Joel Jiang, Christine Horak, Paul Gagnier, Jedd Wolchok, F. Stephen Hodi. Initial report of overall survival rates from a randomized phase II trial evaluating the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma (MEL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT002.