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Higher Rates of Chronic Complications Linked With Anti–PD-1 Treatment Seen in Patients With Melanoma


Results of a multicenter study showed 43% of patients with advanced melanoma treated with anti–programmed cell death 1 therapy experienced chronic complications.

Chronic immune-related adverse events (irAEs) associated with anti–programmed cell death 1 (anti–PD-1) therapy for advanced melanoma are more common than previously recognized and often persist during prolonged follow-up, according to research published in JAMA Oncology.

Although most complications from immunotherapies were low-grade, data showed 43% of patients developed chronic complications, prompting authors to suggest the risks of chronic irAEs be integrated into treatment decision-making. Of those who developed chronic complications, only 14% were resolved at the time of last follow-up.

“Adjuvant treatment with anti–PD-1 improves relapse-free survival (RFS) in patients with resected stage III through IV melanomas,” researchers wrote. “Beyond melanoma, indications for neoadjuvant, adjuvant, and maintenance therapy for anti–PD ligand 1 (PD-L1) are proliferating, also increasing the number of long-term survivors treated with these agents.

Most acute and chronic irAEs associated with anti-PD-L1 agents present within the first 12 weeks of therapy and can be resolved with glucocorticoids. To identify the spectrum, incidence, and kinetics of chronic irAEs that do not fit this characterization, investigators assessed retrospective deidentified data from 8 centers in the United States and Australia.

All patients who were being treated with 1 or more doses of adjuvant anti–PD-1 (pembrolizumab or nivolumab) were included in the study, while “acute irAEs were defined as those developing during treatment, as delayed if arising after completion of treatment, and as chronic if extending 12 or more weeks past treatment discontinuation.”

A total of 387 individuals were included in the analysis, with a median (interquartile range [IQR] age of 63 years (17-88). The majority of patients were male (60.7%) and had preexisting comorbidities (74.9%). In addition, 326 patients received nivolumab and 61 received pembrolizumab monotherapy.

Analyses revealed:

  • 267 (69%) patients had any acute irAE, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity
  • Treatment discontinuation secondary to acute irAEs occurred in 25.8% of patients
  • Chronic irAEs 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.
  • irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs
  • Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs

“In aggregate, 20% of patients experienced symptomatic chronic irAEs (nonendocrinopathies), including some that required persistent immunosuppression,” authors wrote. This could be due to the small volume of affected nonvisceral organs such as hormone-producing endocrine cells, salivary ducts, or eyes, compared with the larger volume of the colon, lungs, or liver. Differential regenerative capacity could also have contributed to this finding, they said.

The retrospective nature of the study marks a limitation. Although both acute and chronic irAEs were linked with improved RFS, this may have been subject to unavoidable biases as there would not be any chronic irAEs in individuals who experienced early progression and death.


Patrinely 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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