Chronic immune-related adverse events (irAEs) associated with adjuvant anti-programmed cell death-1 (anti-PD-1) therapy may be more common than previously reported and frequently persist after prolonged follow-up, although most are low grade, researchers reported in JAMA Oncology.

The retrospective cohort study was conducted at 8 academic medical centers in the United States and Australia from 2015 to 2020. A total of 387 patients with stage III to IV melanomas treated with 1 or more doses of adjuvant anti–PD-1 therapy (pembrolizumab or nivolumab) were included.

The median age of participants was 63 (range, 17-88) years, 235 (60.7%) were male and 290 (74.9%) had preexisting comorbidities. Chronic irAEs were defined as those lasting beyond 12 weeks after treatment discontinuation.

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Treatment was discontinued owing to therapy completion in 193 (50.0%) participants, irAEs in 98 (25.3%) patients, and disease progression in 81 (20.9%) participants. More than two-thirds of the patients had no disease recurrence (268 patients; 69.3%), 69 (17.8%) patients had metastatic recurrences, and 50 (12.9%) patients had metastatic and regional-only recurrences. Patients who had acute or chronic irAEs had a better relapse-free survival (RFS) vs those who did not have an irAE.

From the overall cohort, 276 (69.0%) patients developed acute irAEs, including 171 (44.2%) patients who had grade 2 or higher and 52 (13.4%) patients who had grade 3 to 5 irAEs. Two (0.5%) patients died as a result of irAEs: 1 with myocarditis and 1 with Guillain-Barré–like syndrome.

Patients who had endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (8 of 8; 100%), and ocular events (5 of 8; 63.0%) were more likely to have a chronic event vs patients who had colitis (6 of 44; 13.6%), hepatitis (4 of 25; 16.0%), and pneumonitis (6 of 18; 33.3%). Among all study patients, 167 (43.2%) developed chronic irAEs, with 24 (14.4%) resolving during the follow-up. Almost half (n=82; 49.1%) of the irAEs were symptomatic.

Most of the chronic irAEs were grade 1 or 2 (161 of 167; 96.4%). Among all participants, hypothyroidism (n=54; 14.0%), arthralgias (n=22; 5.7%), dermatitis/pruritus (n=19; 6.6%), adrenal insufficiency (n=12; 3.1%), and xerostomia (n=9; 2.3%) were the most common chronic irAEs.

After assessing each type of chronic irAE for resolution (median follow-up after treatment discontinuation, 287 days), the study authors found that endocrinopathies (73 of 73; 100%), arthralgias (22 of 22; 100%), ocular events (5 of 5; 100%), xerostomia (8 of 9; 88.9%), and cutaneous events (17 of 19; 89.5%) persisted at the last follow-up.

The study’s retrospective design is one of several limitations, according to the investigators. A longer follow-up could potentially show more resolution, and acute and chronic irAEs were associated with improved RFS, which may have been subject to unavoidable biases.

“Adjuvant anti-PD-1 therapy for previously resected advanced melanoma significantly extends RFS,” stated the researchers. “The adjuvant patient population presents unique considerations; they may have been cured by surgery alone and have longer or normal life expectancies. Thus, persistent, life-altering, or life-threatening irAEs should be characterized in detail and integrated into patient counseling and treatment decision-making,” they concluded.

Disclosures: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Patrinely JR Jr, Johnson R, Lawless AR, et al. Chronic immune-related adverse events following adjuvant anti–PD-1 therapy for high-risk resected melanoma. JAMA Oncol. Published online March 25, 2021. doi:10.1001/jamaoncol.2021.0051