Exploring the Clinical Significance of Specific Immune-Related Adverse Events (irAE) in Melanoma Patients Undergoing Immune Checkpoint Inhibitor (ICI) Therapy

Abstract

Abstract Introduction: Several studies have demonstrated that patients who experience irAE as a result of ICI treatment, exhibit significantly improved outcomes compared to patients without toxicity. However, data regarding the impact of specific irAE is currently lacking. Patients and methods: This is a real-world single-site cohort of advanced melanoma patients who were treated with ICI as first line between 2014 and 2020. This study explores the correlation between specific irAE and treatment efficacy. Results: Four hundred and fifteen (415) patients were treated with either anti PD-1 monotherapy (65%), combination of anti PD-1 and anti CTLA-4 (24%), or anti CTLA-4 monotherapy (11%). Median age was 68 years (12-99y), and 58% were male. The median follow-up was 24.5m. Any-grade irAEs were seen in 72% (n = 299), and 26% experienced high-grade irAE (n = 104). The most frequent irAEs were cutaneous (classified as non-vitiligo, n = 110, 26.5% and vitiligo, n = 48, 11.6%), rheumatologic (n = 68, 16.4%), gastrointestinal (n = 66, 15.9%), endocrine (n = 61, 14.7%), and hepatitis (n = 50, 12%). The development of irAE was associated with a significantly longer median PFS (19.6m vs 4.5m; HR 0.46, p < 0.001) and median OS (55m vs 16.9m; HR 0.44, p < 0.001). Specific irAE that were significantly associated with survival benefit were rheumatologic (HR 0.34 for PFS, p < 0.001; HR 0.38 for OS, p < 0.001), non-vitiligo cutaneous (HR 0.58 for PFS, p < 0.001; HR 0.54 for OS, p = 0.001), vitiligo (HR 0.30 for PFS, p < 0.001; HR 0.29 for OS, p < 0.001) and endocrine (HR 0.6 for PFS, p = 0.01; HR 0.52 for OS, p < 0.001). After adjustment for ECOG performance status, LDH level, type of ICI protocol and M-substage - the rheumatologic, non-vitiligo cutaneous and vitiligo irAE remained significant on multivariate analysis for both PFS and OS. Conclusions: The development of rheumatologic, vitiligo and other cutaneous irAE during ICI treatment, is correlated with a noteworthy survival advantage, while other irAE do not present this correlation. These specific irAEs may reflect a hyper-activated immune response and thus can serve as meaningful clinical biomarkers.