title: Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.
abstract: Dermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but they have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the programmed death (PD)-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs are not known.
  
  
  
  We conducted a systematic review of the literature, and performed a meta-analysis of dermatologic AEs observed with the use of pembrolizumab and nivolumab in cancer patients. An electronic search was conducted using the PubMed, and Web of Science, and on the American Society of Clinical Oncology and European Society for Medical Oncology meeting abstracts' libraries for potentially relevant oncology trials, that employed the drugs at Food and Drug Administration-approved doses and reported dermatologic AEs. The incidence, RR and 95% confidence intervals were calculated using either random- or fixed-effects models based on the heterogeneity of included studies. The clinical presentation, histology of affected skin areas, and management strategies (based on institutional experience), are also presented.
  
  
  
  Rash, pruritus and vitiligo were found to be the most frequently reported dermatologic AEs. The calculated incidence of all-grade rash with pembrolizumab and nivolumab was 16.7% (RR = 2.6) and 14.3% (RR = 2.5), respectively. Other significant all-grade AEs included pruritus (pembrolizumab: incidence, 20.2% [RR = 49.9]; nivolumab: incidence, 13.2% [RR = 34.5]) and vitiligo (pembrolizumab: incidence, 8.3% [RR = 17.5]; nivolumab: 7.5% [RR = 14.6]). Interestingly, all the vitiligo events were reported in trials investigating melanoma. The RR for developing dermatologic AEs in general, was 2.95 with pembrolizumab, and 2.3 with nivolumab.
  
  
  
  We found that pembrolizumab and nivolumab are both associated with dermatologic AEs, primarily low-grade rash, pruritus, and vitiligo, which are reminiscent of those seen with ipilimumab. Knowledge of these findings is critical for optimal care, maintaining dose intensity, and health-related quality of life in cancer patients receiving PD-1 inhibitors.
authors.affiliation: Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: V R
authors.initials: VR
authors.lastname: Belum
authors.affiliation: Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; College of Medicine and Life Sciences, University of Toledo, Health Science Campus, 3000 Arlington Avenue, Toledo, OH, USA.
authors.forename: B
authors.initials: B
authors.lastname: Benhuri
authors.affiliation: Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Postow
authors.affiliation: Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Hellmann
authors.affiliation: Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Lesokhin
authors.affiliation: Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Segal
authors.affiliation: Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Motzer
authors.affiliation: Division of Medical Oncology, Department of Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA; Division of Hematology and Oncology, Department of Medicine, Northport VA Medical Center, Northport, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.affiliation: Pathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Busam
authors.affiliation: Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: lacoutum@mskcc.org.
authors.forename: M E
authors.initials: ME
authors.lastname: Lacouture
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002986:Clinical Trials as Topic; D003875:Drug Eruptions / Q000209:etiology*; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D011537:Pruritus / Q000139:chemically induced; D014820:Vitiligo / Q000139:chemically induced; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab
keywords: Adverse events; Immune-checkpoint; Immunotherapy; Nivolumab; PD-1; Pembrolizumab; Programmed death-1; Pruritus; Rash; Vitiligo