Use of Nivolumab plus Ipilimumab Immunotherapy in Patients with Advanced Melanoma
The most recent advancement in the treatment of advanced melanoma is the development of immunotherapies targeting immune checkpoint molecules that are implicated in cancer evasion, such as the programmed death-1 (PD-1) receptor and cytotoxic T-lymphocyte antigen-4 (CTLA-4) nivolumab. Blocking these pathways represents an immunotherapy strategy in cancer therapy that can restore tumor-specific T-cell–mediated immunity. Ipilimumab—a fully human anti–CTLA-4 monoclonal antibody, and nivolumab, a fully human anti–PD-1 antibody—have improved clinical outcomes as single agents in patients with advanced melanoma. At ESMO 2014, Kluger and colleagues presented updated data for survival, efficacy, and clinical activity by BRAF mutation status from a phase 1 clinical trial that evaluated concurrent or sequential therapy with nivolumab plus ipilimumab in several cohorts of patients with advanced melanoma (Kluger et al. ESMO 2014: Abstract 1085O).
In the initial 1-3 concurrent cohorts, 53 patients received nivolumab (0.3, 1.0, or 3.0 mg/kg) every 3 weeks for 8 cycles plus ipilimumab (1 or 3.0 mg/kg) every 3 weeks for 4 cycles as induction; maintenance therapy was then administered with both agents every 12 weeks for 8 doses if patients had no progression by immune-related criteria and no dose-limiting toxicities. An additional 41 patients (cohort 8) received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg at the same induction schedule, then nivolumab 1 mg/kg every 2 weeks for up to 48 doses as maintenance treatment. The 2 sequential cohorts (n = 33) included patients who had received previous standard ipilimumab therapy and who then received maintenance nivolumab 1 or 3 mg/kg every 2 weeks for up to 48 doses (4-12 weeks after last ipilimumab dose).
In the initial concurrent cohort (n = 53), 40% of patients achieved an overall response rate (ORR) by RECIST criteria and 42% demonstrated tumor reduction of ?80% by week 36; the equivalent rates were 43% and 28%, respectively, in cohort 8. Patients in the sequenced cohort also achieved similar responses, with an ORR of 41% by RECIST criteria, including complete response in 6 patients. In the concurrent cohorts 1-3, the 1-year and 2-year overall survival (OS) rates were 85% and 79%, respectively; these OS rates were even higher in cohort 2 (94% and 88%, respectively). By contrast, the 1-year OS rate was lower (70%) in the sequential cohorts; this was hypothesized to be the results of residual levels of plasma ipilimumab.
Retrospective analysis of the clinical responses by BRAF mutation status showed that clinical activity was independent of BRAF mutation status. Safety analysis across all cohorts (n = 94) showed that grade 3 or 4 treatment-related adverse events were reported in 64% of patients; notably, biochemical laboratory abnormalities, including elevations in lipase (15%), ALT (12%), and AST (11%) accounted for the majority of the reported incidence rate.
Kluger and colleagues concluded that the concurrent treatment with nivolumab plus ipilimumab was associated with unprecedented OS rates, which was accompanied by a manageable safety profile in patients with advanced melanoma. Moreover, treatment responses were independent of BRAF mutation status and were durable in many patients.