In a phase II trial reported in the Journal of Clinical Oncology, Olson et al found that pembrolizumab plus low-dose ipilimumab produced durable responses in patients with advanced melanoma whose disease had progressed on immediate prior PD-1 or PD-L1 inhibitor therapy.

Study Details

In the U.S. multicenter study, 70 patients (including 60 who progressed on anti–PD-1 antibody therapy alone and 10 on anti–PD-1/PD-L1 antibody–based combinations [no anti–CTLA-4 combinations permitted]) were enrolled between December 2016 and November 2019. The median duration of prior treatment with anti–PD-1/PD-L1 antibody therapy was 4.8 months. Patients received pembrolizumab at 200 mg plus ipilimumab at 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary endpoint was response rate on immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Responses

Response was observed in 20 patients (29%, 95% confidence interval [CI] = 18.4%–40.6%), including complete response in 5 (7.2%). Median duration of response was 16.6 months (95% CI = 7.9 months–not reached). At the time of data lock, 14 (70%) of 20 responses were ongoing.

No association between time on prior anti–PD-1/PD-L1 antibody therapy and response to study therapy was observed. The median time between prior treatment and start of study treatment was 1.5 months in responders vs 1.4 months in nonresponders. Among patients with known PD-L1 status, response was observed in 15 (38%) of 39 patients with PD-L1–negative tumors and in 4 (15%) of 27 with PD-L1–positive tumors. Assessment of T-cell–inflamed gene expression scores showed that responses occurred in patients with T-cell–inflamed, non–T-cell inflamed, and intermediate tumors.

Median progression-free survival was 5 months (95% CI = 2.8–8.3 months); median overall survival was 24.7 months (95% CI = 15.2 months–not reached).

Adverse Events

Grade 3 to 4 drug-related adverse events occurred in 27% of patients (grade 4 in 1 patient), with the most common being colitis or diarrhea (9%), rash (6%), and transaminase elevations (6%). Treatment-related adverse events leading to treatment discontinuation consisted of transaminase elevation in two patients (3%) and rash, skin/subcutaneous tissue disorder, and colitis/diarrhea in one patient (1%) each. No treatment-related deaths were observed.

The investigators concluded, “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.”

Jason J. Luke, MD, of the University of Pittsburgh Medical Center and Hillman Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Merck Investigator Studies Program. For full disclosures of the study authors, visit ascopubs.org.