Abstract CT101: Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipilimumab-naive advanced melanoma
Authors: Ribas Antoni , Schachter Jacob , Long Georgina V. , Arance Ana , Grob Jean Jacques , Mortier Laurent , Daud Adil , Carlino Matteo S. , McNeil Catriona , Lotem Michal , Larkin James , Lorigan Paul , Neyns Bart , Blank Christian U. , Hamid Omid , Kosh Michele , Zhou Honghong , Ibrahim Nageatte , Ebbinghaus Scot , Robert Caroline 
Published: August 2015

Abstract
Background: Ipilimumab (IPI; anti-CTLA4) and pembrolizumab (PEMBRO; anti-PD-1) are checkpoint inhibitors that stimulate immune responses to cancer. In KEYNOTE-001, PEMBRO showed durable antitumor activity in melanoma patients (pts), regardless of prior IPI treatment. KEYNOTE-006 (NCT01866319) is a pivotal phase III study comparing IPI with 2 PEMBRO dosing regimens in IPI-naive (IPI-N) advanced melanoma pts. Methods: Pts were randomized 1:1:1 to PEMBRO 10 mg/kg Q2W, PEMBRO 10 mg/kg Q3W, or 4 doses of IPI 3 mg/kg Q3W. Randomization was stratified by ECOG PS (0 vs 1), line of therapy (first vs second), and PD-L1 expression (positive [staining in ≥1% of tumor cells] vs negative). BRAFV600-mutant pts naive to BRAF inhibitors were eligible if LDH was normal and there was no evidence of tumor-related symptoms or rapidly progressing disease. PEMBRO was continued until progression, intolerable toxicity, or 24 months. Response was assessed at wk 12 and every 6 wk thereafter per RECIST v1.1 by central review (primary for efficacy) and per immune-related response criteria by investigator review (primary for therapy management). Primary end points are PFS and OS. Secondary end points include ORR and safety. Primary objective of the first interim analysis (IA1), which occurred after completion of enrollment, was to evaluate the superiority of either PEMBRO schedule over IPI for PFS at a 1-sided α = 0.002. IA1 was to be performed when ≥260 PFS events occurred across all arms and all pts had ≥6 mo of follow-up. Differences in PFS and OS were assessed by a stratified log-rank test. Data cutoff date was Sep 3, 2014. The final OS analysis will be performed as the data matures. Results: 834 pts from 16 countries were enrolled between Sep 2013 and Mar 2014; 66% were treatment naive, 80% were PD-L1+, 36% were BRAFV600 mutant, and 69% had ECOG PS 0. Based on 502 PFS events (central RECIST v1.1), both PEMBRO doses demonstrated superiority over IPI (HR 0.58, P &lt; 0.00001 for both PEMBRO doses vs IPI, 95% CIs for HR 0.46-0.72 and 0.47-0.72; HR 0.97, 95% CI 0.77-1.21, P = 0.76 for PEMBRO Q2W vs Q3W). Median follow-up duration was 8 months. The 6-mo PFS rates were 47.3%, 46.4%, and 26.5% for PEMBRO Q3W, PEMBRO Q2W, and IPI. PEMBRO improved OS over IPI after 202 deaths occurred (HR 0.60, 95% CI 0.43-0.84, P = 0.00132 for Q2W; HR 0.56, 95% CI 0.40-0.78, P = 0.00031 for Q3W); 6-mo OS rates were 84.8%, 87.6%, and 74.6%. PFS and OS benefits of PEMBRO were observed across all subgroups assessed. ORR was also improved with PEMBRO (33.7% for Q2W [P = 0.00013], 32.9% for Q3W [P = 0.00002], 11.9% for IPI); responses were ongoing in 89%, 97%, and 88% of pts. The safety profile was consistent with that previously observed for PEMBRO and IPI. Despite a longer duration of therapy, rates of grade 3-5 drug-related AEs were numerically lower in the PEMBRO arms (11.7%) compared with IPI (19.9%). Conclusions: In this first randomized study comparing two immune checkpoint inhibitors, pembrolizumab prolonged PFS and OS and had a favorable safety profile compared with ipilimumab in advanced melanoma pts.
Citation Format: Antoni Ribas, Jacob Schachter, Georgina V. Long, Ana Arance, Jean Jacques Grob, Laurent Mortier, Adil Daud, Matteo S. Carlino, Catriona McNeil, Michal Lotem, James Larkin, Paul Lorigan, Bart Neyns, Christian U. Blank, Omid Hamid, Michele Kosh, Honghong Zhou, Nageatte Ibrahim, Scot Ebbinghaus, Caroline Robert. Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipilimumab-naive advanced melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT101. doi:10.1158/1538-7445.AM2015-CT101