Standard-dose nivolumab in combination with reduced-dose ipilimumab for patients with advanced melanoma

Full text: The combination of Nivolumab 1mg/kg (NIVO1) plus Ipilimumab 3mg/kg (IPI3) has demonstrated better responses rates and progression free survival compared to NIVO alone in first line treatment of advanced melanoma (Checkmate 067). Recently, NIVO1+IPI3 has shown impressive results in select patients with brain metastasis (Checkmate 204). However, this regimen is also associated with extreme high G3/G4 immune-related adverse effects (59%). In attempt to maintain efficacy and reduce toxicity, trials evaluating reduced-dose ipilimumab (1mg/kg) associated with full dose anti-PD1 have been conducted, but with no definitive response to this question (Checkmate 511 and Keynote 029). The aim of this study was to evaluate the objective response rate (ORR) and toxicity of the alternative regimen NIVO 3mg/kg plus IPI 1mg/kg. We conducted a retrospective analysis of patients with advanced melanoma treated in first line setting with this combination at a single center. Survival analysis were calculated with the Kaplan-Meier method. Patients were enrolled from December 2017 to April 2019. The median follow-up was 9.1 months (95% CI: 4.5-13.7). Twenty-one patients were analyzed, 15 male (71.4%), median age of 61.5 (39 to 84 years), 9 (42.9%) with BRAF mutation. 14% / 86% were irresectable stage III / stage IV, respectively. Among stage IV patients, 5 (26.4%) were M1c, 6 (31.6%) M1d (brain metastasis) and 30% had elevated LDH. Liver metastasis accounts for 31.6% of the visceral disease. Response rate was evaluated with CT (28%), PETCT (33%) or both (39%). ORR was 57% (52.4% partial response). Disease control rate (ORR+ SD) was 76%. Progression free and overall survival were 75% and 82% at 12-month analysis, respectively. Median survival time was not reached for both curves at this time point. 62% (13/21) presented adverse events (AEs). Among them, 6/13 (46%) were G3 / G4 (most skin and gastrointestinal AEs). 28% of patients did not complete the induction phase, 33% of those due to toxicity. Fourteen percent of patients discontinued treatment definitively due to toxicity. In conclusion, our study has shown that alternative regimen of NIVO3+IPI1 is associated with similar response rates of the phase III trial of NIVO1+ IPI3 with lower incidence of grade 3 and 4 adverse effects. As limitation of our data, this is a small number of patients and a retrospective analysis. (author)