Antitumor activity of ipilimumab after pembrolizumab in patients with advanced melanoma in KEYNOTE-006

Background: The efficacy and safety of PD-1 inhibition in patients with advanced melanoma previously treated with the CTLA-4 inhibitor ipilimumab has been established in several studies, including the KEYNOTE-001 and 002 trials of pembrolizumab. Conversely, the efficacy of CTLA-4 inhibition with ipilimumab following anti-PD-1 therapy is not clearly established. We assessed outcomes in patients enrolled in KEYNOTE-006 (NCT01866319) who received ipilimumab monotherapy after pembrolizumab. Methods: Patients in KEYNOTE-006 were randomized 1:1:1 to 2 years of pembrolizumab 10 mg/kg Q2W (n = 279) 10 mg/kg Q3W (n = 277) or to 4 doses of ipilimumab 3 mg/kg Q3W (n = 278). Treatment was continued until disease progression, intolerable toxicity, or patient or physician decision. After study treatment discontinuation, subsequent anticancer therapy and outcomes were reported. Results: As of December 3, 2015, ipilimumab was recorded as a subsequent therapy for 129 pembrolizumab-treated patients, including 97 for whom ipilimumab was the first post-study therapy. Of these 97 patients, 64% had M1c disease, 33% had elevated serum LDH at baseline, and 16% had BRAF^V600-mutant tumors at baseline. Best response to pembrolizumab (RECIST v1.1, central review) was PR in 16%, SD in 12%, nonCR/nonPD in 5%, PD in 62%, and nonevaluable/not assessed in 4%. Median duration of pembrolizumab before the start of ipilimumab was 18 weeks (range 0-90), and the median time between the last pembrolizumab dose and first ipilimumab dose was 5 weeks (range 1-42). Median duration of ipilimumab was 8 weeks (range 0-17). The reported ORR for ipilimumab was 14%, with a best overall response of CR in 3%, PR in 11%, SD in 33%, PD in 33%, and unknown in 23%; subsequent progression occurred in 40% of patients with PR and 48% with SD. Best response to pembrolizumab (central RECIST v1.1) in the 13 patients who responded to ipilimumab was SD in 1, nonCR/nonPD in 2, PD in 8, and not assessed in 2. Best response to ipilimumab in the 16 responders to pembrolizumab who received >=1 ipilimumab dose was SD in 8, PD in 3, and unknown in 5. Fifty-seven of 97 patients had died, and median OS from randomization was 19.6 months (95% CI 16.4-23.5). Conclusions: Ipilimumab has antitumor activity following pembrolizumab in patients with advanced melanoma, including those whose best response to pembrolizumab was PD, with an ORR consistent with historical data.