Anti–PD-1 Therapy and Long-Term Toxic Effects Among Patients With Melanoma
10 affiliations
- 1Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia
- 2Vanderbilt University School of Medicine, Nashville, Tennessee
- 3Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia
- 4The Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia
- 5Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
- 6Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC
- 7NYU Langone Health Perlmutter Cancer Center, New York, New York
- 8Department of Medicine, Massachusetts General Hospital, Boston
- 9Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- 10Westmead Hospital, Westmead, New South Wales, Australia
Abstract
Importance: Adjuvant anti–programmed cell death protein 1 (anti–PD-1) treatment improves outcomes in high-risk resected melanoma but causes chronic immune-related adverse events (irAEs) in more than 40% of patients. Risk factors associated with chronic vs acute irAEs remain lacking.
Objective: To identify factors and possible candidate inflammatory pathways associated with the development of chronic nonendocrine irAEs.
Design, Setting, and Participants: This retrospective cohort study was conducted from January 1, 2015, to December 31, 2024, at 7 institutions in the US and Australia. Patients had stage III to IV melanoma treated with adjuvant anti–PD-1 therapy and more than 12 months of follow-up after discontinuation of anti–PD-1 treatment.
Exposures: Potential risk factors (age, sex, time to irAE onset, corticosteroid exposure, time to corticosteroid initiation, peak corticosteroid dose, and anti–PD-1 treatment status) for chronic irAEs.
Main Outcomes and Measures: Incidence, type, and risk factors for chronic (persisting ≥3 months after anti–PD-1 therapy cessation) irAEs and cytokine levels at 12 months after immune checkpoint inhibitor initiation were assessed.
Results: Among 303 patients (median age at anti–PD-1 therapy initiation, 64 years [IQR, 55-72 years]; 184 men [61%]), 220 (73%) developed acute irAEs and 146 (48%) developed chronic irAEs. The most common chronic irAEs were hypothyroidism (45 of 146 [31%]), arthritis (25 of 146 [17%]), and dermatitis (17 of 146 [12%]). Chronic irAEs had later onset (median, 153.0 days [IQR, 67.0-294.0 days] vs 99.0 days [IQR, 32.2-228.8 days]; P = .006) and more frequent corticosteroid exposure (35% [34 of 96] vs 24% [48 of 204]; P = .03) compared with nonchronic irAEs. For exploratory risk factor analysis of 300 nonendocrine irAE events, corticosteroid treatment and onset time had a significant interaction; corticosteroid-treated patients with earlier-onset irAEs had higher odds of developing chronic irAEs (odds ratio, 3.00; 95% CI, 1.45-6.22), adjusted for age, sex, and anti–PD-1 therapy continuation. Eight different cytokines had higher circulating plasma levels among patients with chronic irAEs after false discovery rate (FDR) adjustment (including VEGFA and CCL19), and 19 cytokines had significantly higher circulating plasma levels prior to FDR adjustment. No cytokine levels were higher among controls.
Conclusions and Relevance: In this cohort study of patients with melanoma treated with adjuvant anti–PD-1 therapy, chronic irAEs were common, persistent, and associated with elevated circulating cytokines, suggesting possible candidate inflammatory pathways for future validation. Later irAE onset and corticosteroid-treated irAEs were associated with chronicity of irAEs. Given the long-term survival of these patients, monitoring and managing chronic irAEs is crucial.
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BibTeX
@article{kankaria2026antipd1,
title = {{Anti–PD-1 Therapy and Long-Term Toxic Effects Among Patients With Melanoma}},
author = {Roma A. Kankaria and Reilly Fankhauser and Andrea Boutros and Marlies Pinzon and Kun Bai and Sheau-Chiann Chen and Christian B. Agbisit and Alissa Kalyan and Aleigha Lawless and Georgina V. Long and Ryan J. Sullivan and Janice M. Mehnert and Suthee Rapisuwon and Justin M. Balko and Matteo S. Carlino and Alexander M. Menzies and Douglas B. Johnson},
journal = {JAMA Network Open},
year = {2026},
month = oct,
doi = {10.1001/jamanetworkopen.2026.37199},
url = {https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2854762},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Anti–PD-1 Therapy and Long-Term Toxic Effects Among Patients With Melanoma
AU - Roma A. Kankaria
AU - Reilly Fankhauser
AU - Andrea Boutros
AU - Marlies Pinzon
AU - Kun Bai
AU - Sheau-Chiann Chen
AU - Christian B. Agbisit
AU - Alissa Kalyan
AU - Aleigha Lawless
AU - Georgina V. Long
AU - Ryan J. Sullivan
AU - Janice M. Mehnert
AU - Suthee Rapisuwon
AU - Justin M. Balko
AU - Matteo S. Carlino
AU - Alexander M. Menzies
AU - Douglas B. Johnson
PY - 2026
DA - 2026/10/02
JO - JAMA Network Open
DO - 10.1001/jamanetworkopen.2026.37199
UR - https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2854762
AB - Importance: Adjuvant anti–programmed cell death protein 1 (anti–PD-1) treatment improves outcomes in high-risk resected melanoma but causes chronic immune-related adverse events (irAEs) in more than 40% of patients. Risk factors associated with chronic vs acute irAEs remain lacking. Objective: To identify factors and possible candidate inflammatory pathways associated with the development of chronic nonendocrine irAEs. Design, Setting, and Participants: This retrospective cohort study was conducted from January 1, 2015, to December 31, 2024, at 7 institutions in the US and Australia. Patients had stage III to IV melanoma treated with adjuvant anti–PD-1 therapy and more than 12 months of follow-up after discontinuation of anti–PD-1 treatment. Exposures: Potential risk factors (age, sex, time to irAE onset, corticosteroid exposure, time to corticosteroid initiation, peak corticosteroid dose, and anti–PD-1 treatment status) for chronic irAEs. Main Outcomes and Measures: Incidence, type, and risk factors for chronic (persisting ≥3 months after anti–PD-1 therapy cessation) irAEs and cytokine levels at 12 months after immune checkpoint inhibitor initiation were assessed. Results: Among 303 patients (median age at anti–PD-1 therapy initiation, 64 years [IQR, 55-72 years]; 184 men [61%]), 220 (73%) developed acute irAEs and 146 (48%) developed chronic irAEs. The most common chronic irAEs were hypothyroidism (45 of 146 [31%]), arthritis (25 of 146 [17%]), and dermatitis (17 of 146 [12%]). Chronic irAEs had later onset (median, 153.0 days [IQR, 67.0-294.0 days] vs 99.0 days [IQR, 32.2-228.8 days]; P = .006) and more frequent corticosteroid exposure (35% [34 of 96] vs 24% [48 of 204]; P = .03) compared with nonchronic irAEs. For exploratory risk factor analysis of 300 nonendocrine irAE events, corticosteroid treatment and onset time had a significant interaction; corticosteroid-treated patients with earlier-onset irAEs had higher odds of developing chronic irAEs (odds ratio, 3.00; 95% CI, 1.45-6.22), adjusted for age, sex, and anti–PD-1 therapy continuation. Eight different cytokines had higher circulating plasma levels among patients with chronic irAEs after false discovery rate (FDR) adjustment (including VEGFA and CCL19), and 19 cytokines had significantly higher circulating plasma levels prior to FDR adjustment. No cytokine levels were higher among controls. Conclusions and Relevance: In this cohort study of patients with melanoma treated with adjuvant anti–PD-1 therapy, chronic irAEs were common, persistent, and associated with elevated circulating cytokines, suggesting possible candidate inflammatory pathways for future validation. Later irAE onset and corticosteroid-treated irAEs were associated with chronicity of irAEs. Given the long-term survival of these patients, monitoring and managing chronic irAEs is crucial.
SN - 2574-3805
ER -