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194 A multicenter characterization of chronic toxicities following adjuvant anti-PD-1 therapy for high risk resected melanoma
  1. James Patrinely1,
  2. Rebecca Johnson2,
  3. Aleigha Lawless3,
  4. Prachi Bhave4,
  5. Amelia Sawyers5,
  6. Maya Dimitrova6,
  7. Hui Yeohc7,
  8. Marisa Palmeri8,
  9. Elizabeth Davis9,
  10. Suthee Rapisuwon10,
  11. Georgina Long2,
  12. Andrew Haydon7,
  13. Iman Osman6,
  14. Janice Mehnert6,
  15. Matteo Carlino4,
  16. Ryan Sullivan3,
  17. Alexander Menzies2 and
  18. Douglas Johnson9
  1. 1Vanderbilt University, Nashville, TN, USA
  2. 2Melanoma Institute of Australia, Sydney, Australia
  3. 3Massachusetts General Hospital, Boston, MA, USA
  4. 4Crown Princess Mary Cancer Centre, Sydney, Australia
  5. 5New York University School of Medicine, New York, NY, USA
  6. 6Perlmutter Cancer Center at NYU Langone, New York, NY, USA
  7. 7Alfred Health, Victoria, Australia
  8. 8Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
  9. 9Vanderbilt University Medical Center, Nashville, TN, USA
  10. 10Lombardi Comprehensive Cancer Center, Washington, DC, USA


Background Anti-programmed death-1 (anti-PD-1) therapies have improved long-term survival across many advanced cancers. However, chronic immune-related adverse events (irAEs) are not well-defined. We sought to determine the incidence, time-course, spectrum, and predictors of chronic irAEs arising from adjuvant anti-PD-1.

Methods In this retrospective cohort, we analyzed patients from 8 academic medical centers with stage III-IV melanoma treated with anti-PD-1 in the adjuvant setting. Acute and chronic (persisting at least 3 months after therapy cessation) irAEs were characterized by type, time-course, management, and incidence.

Results Among 387 patients, most were male (60.7%) with a median age of 63 years, had cutaneous primaries (85.8%), BRAF/NRAS WT (51.2%), and resected stage IIIb (33.1%) or IIIc (39.5%) melanomas. Median overall survival and relapse-free survival (RFS) were not reached. 359 patients (93.0%) were alive at median follow-up of 529 days. Patients with acute (p<0.009) or chronic (p<0.001) irAEs had superior RFS compared with patients lacking irAEs. Treatment was discontinued for therapy completion (50.0%), irAEs (25.3%), and disease progression (20.9%). 267 patients (69.0%) had any acute irAE, including 19.5% (n=52) with grade 3–5 events. Acute irAEs were most commonly dermatitis/pruritis (25.8%), thyroiditis/hypothyroid (16.3%), arthralgias (10.6%), colitis/diarrhea (9.8%) and required glucocorticoids in 109 patients (28.2%). Of these, 167 patients (43.2%) developed chronic irAEs; 82 (49.1%) were symptomatic, 55 (32.9%) required glucocorticoids, and most were grade 1–2 (96.4%). Endocrinopathies (73/88, 83.0%) arthritis (22/45, 48.9%), xerostomia (9/17, 52.9%), neurotoxicities (8/8, 100.0%), and ocular events (5/8, 63.0%) were likely to become chronic events. In contrast, colitis (6/44, 13.6%), hepatitis (4/25, 16.0%), pneumonitis (6/18, 33.3%) were less likely to become chronic. Overall, the most common chronic irAEs were hypothyroidism (14.0%), dermatitis/pruritis (6.6%) arthralgias (5.7%), adrenal insufficiency (3.1%), and xerostomia (2.3%). Age (p=0.67), gender (p=0.31), time of onset of acute irAEs (p=0.95), and initial need for glucocorticoids (p=0.15) were not associated with chronicity. Only 24 (14.4%) of chronic irAEs ultimately resolved during the median 529-day follow-up. In particular, endocrinopathies (100%) arthralgias (100%) ocular events (100%), xerostomia (88.9%), and cutaneous events (89.5%) had high rates of persistence at last follow-up.

Conclusions Chronic irAEs to anti-PD-1 were more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low-grade. The risks of chronic toxic effects should be integrated into treatment decision making.

Ethics Approval This study was approved by the Vanderbilt Institutional Review Board

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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