Pembrolizumab Plus Ipilimumab Following Anti-PD-1/L1 Failure in Melanoma

Abstract

PURPOSE Combination of antiprogrammed cell death protein-1 (PD-1) plus anti–cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy. METHODS Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non–anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR. RESULTS Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody–based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1–negative, non-T-cell–inflamed, and intermediate tumor phenotypes. CONCLUSION To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.

Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses

“…42 In a small prospective study of pembrolizumab plus low-dose ipilimumab (1 mg/kg), the ORR was 29% in all enrolled patients. 43 In our study, the DCRs at week 18 were comparable in patients treated with ipilimumab and ipilimumab plus nivolumab. Notably, the elapsed time interval between the last dose of anti-PD-1 monotherapy and the study drug was short in both arms: 6 weeks (range 3–55 weeks) in patients treated with ipilimumab arm and 4.3 (range 2–36 weeks) in patients treated with ipilimumab plus nivolumab.…”

Signal pathways of melanoma and targeted therapy

“… 551 Of note, improved antitumor response and tolerable safety are seen in anti-PD-1/PD-L1-refractory melanoma patients with pembrolizumab plus low-dose ipilimumab. 552 The treatment of other types of melanoma excluding cutaneous melanoma is of great challenge for their relatively insensitive response to existing therapies. The combination of nivolumab and ipilimumab has been subsequently evaluated in non-cutaneous melanoma including acral, mucosal, and uveal melanoma, and the combination regimen shows sustained and improved response compared with either single agent, although with elevated toxicity but manageable safety profile.…”

Various Uses of PD1/PD-L1 Inhibitor in Oncology: Opportunities and Challenges

“…This combination approach has become the most intensively studied as well as the most widely used immune combination regimen (103). Daniel et al (104) evaluated the efficacy of Pembrolizumab plus Ipilimumab in melanoma patients after failure of anti-PD-1/PD-L1 therapy and showed that 29% of patients achieved a confirmed response (including 21.4% partial responses and 7.2% complete responses). This demonstrates the significant antitumor activity of the combination.…”