Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of hormone replacement and immunosuppressants, and association with outcome: E1609 study analysis.

Abstract

60 Background: E1609 evaluated adjuvant ipilimumab at 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus high-dose interferon-α (HDI). In-depth analysis of irAEs and the use of immunosuppressants and hormone replacement may provide important lessons for management and future research. Methods: E1609 enrolled 1670 adult pts with resected cutaneous melanoma (AJCC7 IIIB, IIIC, M1a, M1b); Table. We investigated the characteristics of irAEs, corticosteroid, immunosuppressant and hormone use on the ipi arms and association with outcome. Stratified log-rank test was used and since most irAEs were observed within 3 months of initiating ipi, a 3-month landmark adjustment analysis was conducted. Results: The rates of corticosteroid, immunosuppressant and hormone use by treatment are summarized in Table and none had a significant association with RFS or OS. Significant association between occurrence of grade 1-4 irAEs (vs. no AE) and RFS was observed [5-year RFS: 0.49, 95% CI: (0.45, 0.52) compared to 0.41, 95% CI: (0.31, 0.50); landmark p=0.010]. Occurrence of grade 1-2 irAEs appeared to have a stronger association with RFS [5-years RFS: 0.52, 95% CI: (0.47, 0.56) compared to 0.41, 95% CI: (0.31,0.50) with no AE; p=0.006] and a trend towards improved OS [5-year OS: 0.75, 95%CI:( 0.71, 0.79) compared to 0.67, 95% CI: (0.56, 0.75) with no AE; p=0.064]. Among specific irAEs, rash was most significantly associated with RFS (p = 0.004 and 0.002) and OS (p = 0.007 and 0.003) for grade 1-4 and grade 1-2, respectively, followed by endocrinopathies, and weaker associations seen with other AEs. Conclusions: Adjuvant therapy with ipi is associated with significant irAEs that appear to be related to the immune mechanism of action. Corticosteroids and immunosuppressants were not shown to negatively affect the clinical outcomes. Predictors of irAE risk and understanding the underlying mechanisms are a major gap and are currently actively being investigated. Clinical trial information: NCT01274338. [Table: see text]