Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes

Purpose: Retrospective analysis of irAEs in melanoma patients treated with nivolumab. Experimental Design: Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of immune-related adverse events (irAE) were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in overall survival (OS) in the presence or absence of irAEs. Results: IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically significant OS difference was noted among patients with any grade of irAE versus those without (P <= 0.001), and OS benefit was noted in patients who reported three or more irAE events (P <= 0.001). Subset analyses showed statistically significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence interval (CI), 0.243-0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI, 0.036-0.94). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (P = 0.004 and P = 0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis). Conclusions: Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses. (C) 2015 AACR.