Three PD-1 inhibitors are in midstage clinical development for metastatic melanoma and other solid tumors: nivolumab, pembrolizumab (PEM), and pidilizumab. Ribas and colleagues presented late-breaking data regarding PEM, including its safety and efficacy in a large phase 1 trial in metastatic melanoma (ASCO 2014; Abstract 9000). This phase 1 study of PEM enrolled 411 patients with metastatic melanoma, including more than 200 patients who had previously been treated with ipilimumab (IPI), an anti-CTLA-4 antibody.
Overall, 34% of patients with metastatic melanoma experienced complete or partial responses to PEM as assessed by independent reviewers. Response rates were 40% in patients who had not received IPI, and 28% in patients whose disease progressed after receiving IPI, a difference that did not reach statistical significance. Most patients who received PEM responded at the time of the first tumor assessment at 10 weeks. Responses were durable, with 88% ongoing at the time of analysis.
Activity of PEM was observed across all dose levels and patient subgroups, irrespective of performance status, lactate dehydrogenase levels, BRAF mutation status, melanoma stage, and number and type of prior therapies. Dr Ribas noted that tumor size at baseline was found to correlate with response to PEM, such that smaller tumors at baseline were more likely to respond (Abstract 3015 at ASCO 2014 provides more detail).
In this phase 1 study of PEM in metastatic melanoma, the 1-year overall survival (OS) rate was 69%, including all patient subgroups and PEM dose schedules. The 18-month OS rate was 62%. Responses were ongoing in 88% of patients after a median follow-up of 12 months; median OS has not yet been reached. The estimated 1-year survival rate was 74% in patients not previously treated with IPI and 65% in patients who received prior IPI, a difference that was not statistically significant.
Eight percent of melanoma patients experienced serious treatment-related adverse events (AEs), but only 4% discontinued treatment due to a drug-related AE. Grade 3/4 immune-related AEs, such as hypothyroiditis and colitis, occurred at rates less than 1%.
Ongoing randomized controlled studies are assessing the efficacy and safety of PEM in advanced melanoma patients not previously treated with IPI, as well as patients who progressed on or after receiving IPI. Studies of PEM in the adjuvant melanoma setting are also planned. The press release from ASCO regarding this study noted that an expanded access program for PEM is now available for eligible patients with advanced melanoma who have been previously treated with IPI and, if relevant, a BRAF inhibitor.
