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Immune checkpoint blockade is widely validated as effective for advanced melanoma of both BRAF-mutated and BRAF-normal genotypes. Three immunotherapy agents are approved: the anti–programmed cell death 1 (anti-PD-1) antibodies pembrolizumab and nivolumab and the anti–cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) ipilimumab. To identify the most effective treatment, investigators tested ipilimumab monotherapy against pembrolizumab or ipilimumab+nivolumab.
Robert and colleagues assigned 834 patients to pembrolizumab (10 mg/kg every 2 or 3 weeks) or ipilimumab (3 mg/kg every 3 weeks). Both pembrolizumab regimens significantly prolonged progression-free survival (estimated rates at 6 months were 47.3% and 46.4% for pembrolizumab every 2 and 3 weeks and 26.5% for ipilimumab). Drug-associated grade 3 to 5 adverse effects occurred in 13.3%, 10.1%, and 19.9% of the groups, respectively. Overall survival was significantly better with pembrolizumab (estimated hazard ratios at 1 year for death in pembrolizumab recipients vs. ipilimumab recipients were 0.63–0.69).
Postow and colleagues assigned 142 patients with untreated metastatic melanoma to ipilimumab+nivolumab (combined treatment) or ipilimumab+placebo (monotherapy) until occurrence of disease progression or unacceptable toxic effects. Patients with BRAF wild-type tumors who received combined treatment had confirmed objective response rates of 61%, versus 11% in monotherapy recipients (P<0.001); 22% of combined-treatment recipients and no monotherapy recipients had complete responses. The median progression-free survival was not reached with combination therapy; it was 4.4 months with monotherapy. Rates were similar for patients with BRAF-mutated tumors. Grade 3 to 4 drug-related adverse effects occurred in 54% of combined-therapy recipients versus 24% of monotherapy recipients.
Robert C et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015 Apr 19; [e-pub]. (http://dx.doi.org/10.1056/NEJMoa1503093)
Postow MA et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015 Apr 20; [e-pub]. (http://dx.doi.org/10.1056/NEJMoa1414428)
Comment
Both studies clearly show superiority of anti-PD-1 drugs for advanced melanoma. It is worth noting that grade 3 to 4 adverse events were observed in more than half of nivolumab+ipilimumab recipients but were much less common in pembrolizumab recipients. The pembrolizumab trial included patients with BRAF-mutated tumors who had undergone previous BRAF-inhibitor treatment. Tumors with high PD-L1 may benefit more from anti-PD-1 treatments. Thus, in pembrolizumab and nivolumab, we appear to have treatment that is agnostic to mutational status and prior treatment, is more effective than ipilimumab, has a better safety profile, and has a tangible marker of response (anti-PD-L1). However, ipilimumab has been around longer and is better characterized; the long-term duration of benefit is not as well known for the anti-PD-1 drugs.