Nivolumab maintenance improves overall survival of patients with advanced melanoma who experience severe immune-related adverse events on nivolumab plus ipilimumab

Abstract

Background The combination of ipilimumab and nivolumab is a highly effective treatment for metastatic cutaneous melanoma. However, immune-related adverse events (irAEs) are common, often necessitating treatment interruption and the use of immunosuppressive agents. There is no data on the impact of resuming nivolumab on survival following recovery from the irAE and completion of immunosuppressive treatment.Patients and methods In this retrospective analysis, we examined a cohort of patients treated with ipilimumab/nivolumab who developed irAEs requiring treatment interruption and immunosuppressive therapy. The differences in physician practice patterns at our institution allowed us to examine the survival effect of restarting single-agent nivolumab. A multivariate analysis of clinical factors associated with improved survival was performed.Results We identified 165 patients who were treated with ipilimumab/nivolumab and developed irAEs requiring treatment interruption and immunosuppressive therapy. Patients with the best overall response of progressive disease were excluded. Of the remaining 122 patients, 46 resumed single-agent nivolumab. When stratified by age and adjusted for sex, M-stage, lactate dehydrogenase (LDH), therapy duration, and irAE type, the effect of resumption of nivolumab on survival was highly significant (p=0.02). Patients who resumed nivolumab had a 68% reduction in the hazard of death compared with patients who had not yet or never resumed nivolumab (HR: 0.32, 95% CI: 0.12 to 0.84). Of the patients who resumed nivolumab, 12 (26%) patients had subsequent irAEs, with five patients having grade 3 irAEs. No grade 4 or 5 irAEs were noted.Conclusions Resuming single-agent nivolumab following a treatment interruption for ipilimumab/nivolumab-associated irAE and completion of immunosuppressive therapy increased overall survival compared with discontinuing nivolumab permanently in patients with metastatic melanoma. Toxicity observed post-resumption of single-agent nivolumab was manageable with no severe irAEs observed.