Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma.

Importance Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies. Objectives To evaluate the risk of a recurrence of immune toxic effects associated with anti–programmed cell death 1 antibody (anti–PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs. Design, Settings, and Participants This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti–PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017. Exposures Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti–PD-1 (nivolumab or pembrolizumab) therapy. Main Outcomes and Measures The primary outcome was the rate of immune-related AEs associated with anti–PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti–PD-1 immune–related AEs and overall response rate and overall survival associated with anti–PD-1 therapy. Results Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti–tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti–PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing). Conclusions and Relevance The findings suggest that anti–PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.