J Randall Patrinely1, Rebecca Johnson2,3, Aleigha R Lawless4, Prachi Bhave2,5, Amelia Sawyers6, Maya Dimitrova7, Hui Ling Yeoh8, Marisa Palmeri9, Fei Ye10, Run Fan10, Elizabeth J Davis11, Suthee Rapisuwon12, Georgina V Long2,3, Andrew Haydon8, Iman Osman7, Janice M Mehnert7,9, Matteo S Carlino5, Ryan J Sullivan4, Alexander M Menzies2,3, Douglas B Johnson11. 1. School of Medicine, Vanderbilt University, Nashville, Tennessee. 2. Melanoma Institute of Australia, The University of Sydney, Sydney, New South Wales, Australia. 3. Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia. 4. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston. 5. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia. 6. Ronald O. Perelman Department of Dermatology, NYU Langone Health, New York University School of Medicine, New York, New York. 7. Division of Hematology and Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York University School of Medicine, New York, New York. 8. Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia. 9. Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick. 10. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee. 11. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. 12. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
Abstract
Importance: Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective: To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures: Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results: Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, 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. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance: In this multicenter cohort study, chronic irAEs 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 irAEs should be integrated into treatment decision-making.
Importance: Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective: To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures: Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results: Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, 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. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance: In this multicenter cohort study, chronic irAEs 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 irAEs should be integrated into treatment decision-making.
Authors: Michelle A Mollica; Ashley Wilder Smith; Emily Tonorezos; Kathleen Castro; Kelly K Filipski; Jennifer Guida; Frank Perna; Paige Green; Paul B Jacobsen; Angela Mariotto; Gina Tesauro; Lisa Gallicchio Journal: J Natl Cancer Inst Date: 2022-04-11 Impact factor: 13.506
Authors: Zishuo Ian Hu; Verena M Link; Djalma S Lima-Junior; Jérémie Delaleu; Nicolas Bouladoux; Seong-Ji Han; Nicholas Collins; Yasmine Belkaid Journal: Proc Natl Acad Sci U S A Date: 2022-06-21 Impact factor: 12.779
Authors: Daan C L Vessies; Milou M F Schuurbiers; Vincent van der Noort; Irene Schouten; Theodora C Linders; Mirthe Lanfermeijer; Kalpana L Ramkisoensing; Koen J Hartemink; Kim Monkhorst; Michel M van den Heuvel; Daan van den Broek Journal: Mol Oncol Date: 2022-06-27 Impact factor: 7.449