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Predicting Immune-related Adverse Events from Checkpoint Inhibitors in Melanoma

Helen Leask



Routine histopathology reports may allow physicians to predict which patients with melanoma are the most likely to develop immune-related adverse events while taking checkpoint inhibitors.


  • Immune checkpoint inhibitors ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) used in advanced melanoma can trigger immune-related adverse events, complications that can be prolonged and sometimes irreversible.
  • This study evaluated the predictive role of melanoma histopathology to identify the risk factors for immune-related adverse events.
  • The retrospective chart review scoured records from 511 patients who had been treated with checkpoint inhibitors for melanoma in three centers in the United States.
  • The authors used two-stage regression analysis to investigate any associations between immune-related adverse events and eight aspects of tumor histopathology (tumor-infiltrating lymphocytes, regression, ulceration, mitotic rate, lymphovascular invasion, histological subtype, anatomic location, and BRAF/NRAS mutation).


  • The most used first-line checkpoint inhibitors were pembrolizumab (44.0%) and nivolumab (23.5%), and approximately 40% of patients stopped or changed checkpoint inhibitors due to immune-related adverse events.
  • Most patients (71.4%) experienced all-grade toxicities, and 28.2% experienced high-grade toxicities.
  • Two histopathological features were associated with all-grade immune-related adverse events. Patients with indeterminate lymphovascular invasion had significantly lower odds of developing all-grade immune-related adverse events than patients with lymphovascular invasion (adjusted odds ratio [aOR], 0.36), and the presence of NRAS mutation increased the patients' odds of developing all-grade immune-related adverse events (aOR, 2.56).
  • None of the histopathologies significantly predicted high-grade immune-related adverse events.


The authors concluded that the presence of lymphovascular invasion and NRAS mutation were associated with increased odds of all-grade immune-related adverse events but did not make any practice recommendations.


The first author was Catherina X. Pan, BA, and joint senior authors were Vinod E. Nambudiri, MD, and Nicole R. LeBoeuf, MD, all of Brigham and Women's Hospital Department of Dermatology, Boston, Massachusetts. The research was supported in part by the Office of Scholarly Engagement, Harvard Medical School, Boston, and prepublished on November 29, 2023, in the Journal of the American Academy of Dermatology.


The analysis was retrospective and may not be generalizable because of institutional variation in the interpretation of histopathology reports.


LeBoeuf is a consultant and has received honoraria from Bayer, Seattle Genetics, Sanofi, Fortress Biotech, Silverback, and Synox Therapeutics. Co-author Daniel Y. Kim, BS, is a scientific consultant at Verve Therapeutics and SeQure Dx. The other authors declared no competing interests.



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