Chronic IRAEs With Adjuvant Anti–PD-1 Therapy More Common Than Previously Understood for Resected Melanoma

The study concluded that immune-related adverse events were more common than previously anticipated following adjuvant anti–PD-1 therapy and persisted with prolonged follow-up.

Data analyzing chronic immune-related adverse events (irAEs) following adjuvant anti–PD-1 therapy was found to be more common than previously anticipated for patients with high-risk resected melanoma, according to data published in JAMA Oncology.

The multicenter cohort study also found that the chronic irAEs associated with anti–PD-1 therapy frequently persisted with prolonged follow-up, but the investigative team noted the irAES were typically low grade.

“Patients treated with anti–PD-1 therapy increasingly experience long-term survival. To our knowledge, this is the largest characterization of chronic irAEs from anti–PD-1 to date,” wrote the investigators. “We conclude that chronic irAEs, while usually low grade, occur more frequently than previously reported and particularly affect nonvisceral organs.”

The study included 387 patients who were mostly male (60.7%) and had a median age of 63 years (range, 17-88). Of this cohort, 267 patients had acute irAEs, which were defined as “those arising during treatment with anti–PD-1.” Fifty-two patients had events categorized as grade 3 through 5 in severity. Chronic irAEs were defined as “those that persisted beyond 12 weeks of anti–PD-1 discontinuation.”

Overall, chronic irAEs developed in 167 patients, with most events categorized as mild, being either grade 1 or 2 in severity (96.4%) and persisting until the last available follow-up (85.6%). The irAEs most commonly converting to chronic included endocrinopathies (83.0% of patients), arthritis (48.9%), xerostomia (52.9%), neurotoxicities (73.3%), and ocular events (62.5%).

Comparatively, irAEs that impacted visceral organs had significantly lower rates of becoming chronic. The investigative team also reported that age, gender, time of onset, and need for steroids were not associated with the likelihood of irAEs becoming chronic.

“This is the first study to systematically examine anti–PD-1–related chronic irAEs in patients with high-risk, resected melanomas,” wrote the investigators. “Results demonstrated that nearly half of patients developed a chronic irAE, with most unresolved at last follow-up.”

This study collected data in a retrospective fashion across 8 academic medical centers in the United States and Australia between 2015 and 2020. The patient cohort included those with stage 3 or 4 melanomas treated with anti–PD-1 in the adjuvant setting.

Limitations of the research included the retrospective design of the study and the limited follow-up time of the data. More, the investigative team observed that both acute and chronic irAEs were associated with improved relapse-free survival, which could subject the team to unavoidable biases.

“Chronic irAEs associated with anti–PD-1therapy are more common than previously recognized and frequently persist even with prolonged follow-up,” concluded the investigators.


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

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