Chronic Immune-Related Adverse Events Associated With Adjuvant Immunotherapy for Advanced Melanoma

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In a retrospective cohort study reported in JAMA Oncology, Patrinely et al found that chronic immune-related adverse events occurred in a high proportion of patients receiving adjuvant PD-1–targeted therapy for high-risk resected melanoma and frequently persisted even during prolonged follow-up. However, most were of a low grade.

Study Details

The study involved data from 387 patients with resected stage III or IV melanoma from eight sites in the United States and Australia who received adjuvant anti–PD-1 treatment between 2015 and 2020. Chronic immune-related adverse events were defined as those persisting for ≥ 12 weeks after discontinuation of anti–PD-1 treatment.

Key Findings

Among the 387 patients, 267 (69.0%) had acute immune-related adverse events (occurring during treatment); 52 (19.5%) had grade ≥ 3 events, with 1 patient each dying from immune-related myocarditis and neurotoxicity, respectively.

Acute immune-related adverse events included dermatitis/pruritus in 25.8% of patients, thyroiditis/hypothyroidism in 16.3%, arthralgias in 10.6%, colitis/diarrhea in 9.8%, hepatitis in 6.2%, pneumonitis in 4.4%, and xerostomia in 4.1%. Glucocorticoid treatment was required in 28.2% of all patients.


  • Chronic immune-related adverse events developed in 167 of 387 total patients (43.2%) and were grade 1 or 2 in 161 (96.4%).
  • Chronic immune-related adverse events persisted until last follow-up in 143 patients, with higher rates of persistence for endocrinopathies, arthralgias, ocular events, xerostomia, and cutaneous events.

Median follow-up was 529 days. Chronic immune-related adverse events developed in 167 patients (43.2%) and were grade 1 or 2 in 161 (96.4%). Chronic events included hypothyroidism in 14.0% of patients, arthralgias in 5.7%, dermatitis/pruritus in 6.6%, adrenal insufficiency in 3.1%, and xerostomia in 2.3%; a range of persistent events were observed in nearly every organ system. Glucocorticoid treatment was required in 32.9% of patients with chronic events.

Median follow-up after treatment discontinuation was 287 days. In total, chronic immune-related adverse events persisted until last follow-up in 143 patients (85.6%), with higher rates of persistence for endocrinopathies (73/73, 100%), arthralgias (22/22, 100%), ocular events (5/5, 100%), xerostomia (8/9, 88.9%), and cutaneous events (17/19, 89.5%); lower rates were seen for colitis (2/6, 33.3%), neuropathies (1/3, 33.3%), and nephritis (1/3, 33.3%).

Patients with endocrinopathies (73/88, 83.0%), arthritis (22/45, 48.9%), xerostomia (9/17, 52.9%), neurotoxicities (8/8, 100%), and ocular events (5/8, 63.0%) were more likely to develop chronic immune-related adverse events. Events affecting visceral organs were less likely to become chronic, including colitis (6/44, 13.6%), hepatitis (4/25, 16.0%), and pneumonitis (6/18, 33.3%).

There were no differences between patients who did vs did not develop chronic immune-related adverse events with regard to age (median = 63.0 vs 63.0 years, P = .67), sex (41.2% male vs 46.1% female, P = .31), or median time of onset of acute immune-related adverse events (84 vs 73 days, P = .95). Excluding endocrinopathies, patients who received vs did not receive glucocorticoids for acute immune-related adverse events were not more likely to develop chronic events (59.6% vs 50.0%, P = .15).

The investigators concluded: “In this multicenter cohort study, chronic immune-related adverse events 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 immune-related adverse events should be integrated into treatment decision-making.”

Douglas B. Johnson, MD, of Vanderbilt University Medical Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the Cancer Institute of New South Wales, Melanoma Institute of Australia, National Health and Medical Research Council, American Cancer Society, National Institutes of Health, and others. For full disclosures of the study authors, visit

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