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

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 t...

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Published in:	European journal of cancer (1990) Vol. 60; pp. 12 - 25
Main Authors:	Belum, V.R, Benhuri, B, Postow, M.A, Hellmann, M.D, Lesokhin, A.M, Segal, N.H, Motzer, R.J, Wu, S, Busam, K.J, Wolchok, J.D, Lacouture, M.E
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-06-2016
Subjects:	Adolescent Adult Adverse events Aged Aged, 80 and over Antibodies, Monoclonal - adverse effects Antibodies, Monoclonal, Humanized - adverse effects Antineoplastic Agents - adverse effects Cell Cycle Checkpoints - drug effects Clinical Trials as Topic Drug Eruptions - etiology Exanthema - chemically induced Female Hematology, Oncology and Palliative Medicine Humans Immune-checkpoint Immunotherapy Male Middle Aged Neoplasms - drug therapy Nivolumab PD-1 Pembrolizumab Programmed Cell Death 1 Receptor - antagonists & inhibitors Programmed death-1 Pruritus Pruritus - chemically induced Rash Vitiligo Vitiligo - chemically induced Young Adult Immune-checkpoint Pembrolizumab Rash Vitiligo Adverse events Immunotherapy Nivolumab Pruritus PD-1 Programmed death-1
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Summary:	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.
Bibliography:	These authors, VRB and BB, contributed equally to this manuscript, and should be regarded as Joint First Authors.
ISSN:	0959-8049 1879-0852
DOI:	10.1016/j.ejca.2016.02.010