Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials

Abstract

Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.

Fig 1.

Patient populations included in this pooled analysis. (*) Includes patients who discontinued and had a treatment-related adverse event (AE) at any time. (†) For patients who had taken at least one dose of nivolumab monotherapy, the induction phase was defined as the time between the first dose of nivolumab plus ipilimumab up to a day before the first nivolumab monotherapy dose. For patients who discontinued before receiving nivolumab monotherapy, the induction phase was defined as the time between the first and the last dose of combination treatment.

Fig 2.

Time to and duration of response in patients who discontinued treatment because of adverse events during the induction phase of treatment.

Fig 3.

(A) Progression-free survival and (B) overall survival for patients who discontinued treatment because of adverse events (AEs) during the induction phase and for patients who did not discontinue because of AEs. Differences between the two subgroups were not statistically significant for either progression-free survival or overall survival.

Fig 4.

Time to onset of treatment-related select grade 3 or 4 adverse events in all patients with one or more events and resolution of treatment-related select grade 3 or 4 adverse events in patients treated with immune-modulating medication. DC, discontinuation.