Low-Dose Ipilimumab/Pembrolizumab Reduces Toxicity in Advanced Melanoma

A combination of pembrolizumab and low-dose ipilimumab appears to be active and to have a better safety profile than a combination of nivolumab and full-dose ipilimumab in advanced melanoma patients, according to a new study presented at the Society for Melanoma Research 2015 International Congress, held November 18–21 in San Francisco.

Pembrolizumab is a potent, highly selective, humanized monoclonal antibody against programmed death-1 (PD-1) that has shown robust antitumor activity against several advanced malignancies. In phase I testing, combination therapy with the anti–PD-1 antibody nivolumab and full doses (3 mg/kg) of the anti–CTLA-4 therapy ipilimumab was seemingly associated with improved response rates, but also led to increased toxicities, said Georgina Long, BSc, PhD, MBBS, of the Melanoma Institute Australia in Sydney, Australia.

Dr. Long and colleagues proposed that full-dose anti–PD-1 therapy with pembrolizumab plus low-dose therapy with ipilimumab would lead to decreased toxicity while maintaining efficacy.

The KEYNOTE-029 trial is a phase I/II study of pembrolizumab 2 mg/kg every 3 weeks for up to 2 years plus low-dose ipilimumab 1 mg/kg every 3 weeks for four doses. The dose run-in phase included patients with advanced melanoma or advanced renal cell carcinoma with one or more prior therapy (no prior anti–CTLA-4 or anti–PD-1/PD-L1 therapies) and good performance status. If the regimen was tolerated, then patients were enrolled in the dose expansion phase.

Dr. Long reported results on 72 melanoma patients, median age 60, with a follow-up duration of at least 18 weeks. She noted that 12% of the patients had received prior therapies. More than two-thirds (69%) of the patients were on pembrolizumab and nearly three-quarters (72%) of them received all four doses of ipilimumab.

The overall response rate (ORR) was 56% and the disease control rate was 79%, including 37 partial responses and 3 complete responses.

Virtually all (93%) of the patients had treatment-related adverse events, but only 36% had grade 3/4 events; 22% were serious events. The most common treatment-related adverse events were rash, fatigue, and pruritus. Using standard measurement algorithms, about two-thirds of any grade (63%) and grade 3/4 (67%) treatment-related adverse events resolved, she said.

About half the patients (54%) had immune-mediated adverse events, and 17% were of grade 3/4.

In conclusion, Dr. Long said: “The combination of pembrolizumab and low-dose ipilimumab is tolerable, and provided an ORR that is comparable to that previously reported for nivolumab and full-dose ipilimumab.” Efficacy, safety, and biomarkers will be further analyzed in a full expansion cohort of 153 patients.

When asked to compare the safety of this trial to the previous phase III trial with nivolumab and full-dose ipilimumab, Dr. Long noted the earlier combination induced grade 3/4 treatment-related adverse events in 55% of patients. “In this trial, we saw only 36% grade 3/4 treatment-related adverse events. The data are still early. We need to see how things evolve,” she said.