Programmed cell death 1 (PD-1) inhibitors such as pembrolizumab and nivolumab, as monotherapy or in combination with ipilimumab, are better first-line therapies than ipilimumab alone in patients with advanced melanoma, data presented at the American Association for Cancer Research (AACR) 2015 Annual Meeting have shown.

In the phase III KEYNOTE-006 trial (n=834; 65.8 percent previously untreated), pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS) and response rates (RRs) vs ipilimumab, an inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) that is currently a standard first-line therapy for advanced melanoma. [N Engl J Med 2015, doi: 10.1056/NEJMoa1503093]

At 6 months, estimated PFS rates were 47.3 percent for pembrolizumab 10 mg/kg every 2 weeks and 46.4 percent for pembrolizumab 10 mg/kg every 3 weeks, compared with 26.5 percent for ipilimumab (3 mg/kg, 4 doses every 3 weeks) (hazard ratio [HR], 0.58; p<0.001).

“At 12 months, estimated OS rates were 74.1 percent for pembrolizumab every 2 weeks [HR, 0.63; p=0.0005] and 68.4 percent for pembrolizumab every 3 weeks [HR, 0.69; p=0.0036], vs 58.2 percent for ipilimumab,” reported lead author Dr. Antoni Ribas of the University of California, Los Angeles, CA, US.

RRs were also higher with pembrolizumab (33.7 percent for 2-weekly dosing, 32.9 percent for 3-weekly dosing) vs ipilimumab (11.9 percent; p<0.001).

Treatment-related grade 3-5 adverse events (AEs) were less common with pembrolizumab (13.3 and 10.1 percent for 2-weekly and 3-weekly dosing, respectively) than ipilimumab (19.9 percent).

“These results exceeded our expectations of the benefit of pembrolizumab over ipilimumab,” said Ribas. “The data will change the paradigm of treatment of advanced melanoma.”

Nivolumab, when used in combination with ipilimumab, also showed significant benefits over ipilimumab in patients with previously untreated advanced melanoma.

In a phase II trial of 142 patients, PFS and objective response rate (ORR) were significantly improved with the nivolumab/ipilimumab combination vs ipilimumab alone. [N Engl J Med 2015, doi: 10.1056/NEJMoa1414428]

“Among 109 patients with BRAF wild-type tumours, median PFS was not reached in the combination therapy arm vs 4.4 months with ipilimumab monotherapy [HR, 0.40; p<0.001],” reported lead investigator Dr. Stephen Hodi of the Dana-Farber Cancer Institute in Boston, MA, US.

ORR was 61 percent with combination therapy vs 11 percent with ipilimumab monotherapy (p<0.001). “Importantly, 22 percent of patients achieved complete response with the combination regimen,” said Hodi. “There were no complete responses with ipilimumab monotherapy.”

The investigators reported similar results for PFS and ORR in the 33 patients with BRAF V600 mutation-positive tumours. Again, 22 percent of patients achieved complete response with combination therapy.

However, the combination regimen was associated with higher rates of grade 3/4 drug-related AEs (54 percent vs 24 percent for ipilimumab monotherapy).

Pembrolizumab and nivolumab are currently approved by the US FDA for treatment of unresectable or metastatic melanoma that progressed after treatment with ipilimumab or a BRAF inhibitor.