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Eur J Cancer. 2016 Jun;60:12-25. doi: 10.1016/j.ejca.2016.02.010. Epub 2016 Apr 1.

Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor.

Author information

1
Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
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.
3
Melanoma and Immunotherapeutics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
4
Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
5
Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
6
Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
7
Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
8
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.
9
Pathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
10
Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: lacoutum@mskcc.org.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

Adverse events; Immune-checkpoint; Immunotherapy; Nivolumab; PD-1; Pembrolizumab; Programmed death-1; Pruritus; Rash; Vitiligo

PMID:
27043866
PMCID:
PMC4998047
DOI:
10.1016/j.ejca.2016.02.010
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

STATEMENT VRB, BB, MDH, NHS, RJM, and KJB have no conflicts of interest to declare. MAP has had a consulting or advisory role with Amgen and Bristol-Myers Squibb, and receives research support from Bristol-Myers Squibb and Novartis (Inst). AML has a consulting or advisory role with Bristol-Myers Squibb, Janssen, Aduro, Efranat, Jounce, and Novartis, and receives research funding from Bristol-Myers Squibb (Inst), Janssen (Inst.), and Genentech (Inst). SW has a speaking arrangement with Novartis, Bayer-Onyx, Pfizer, and Mediavation. JDW has a consulting or advisory role with Bristol-Myers Squibb, Merck, MedImmune, Ziopharm, Polynoma, Polaris, Jounce, GlaxoSmithKline; receives honoraria from EMD Serono, Janssen Oncology, and research funding from Bristol-Myers Squibb (Inst), MedImmune (Inst), GlaxoSmithKline (Inst), Merck (Inst). MEL has consulted for BMS and Merck, and received research support from Bristol-Myers Squibb (Inst).

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