Chronic Immune-Related Adverse Events Following Adjuvant Anti–PD-1 Therapy for High-risk Resected Melanoma

Abstract

Importance: Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective: To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures: Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results: Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance: In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.