Adverse Dermal Effects of PD-1 Inhibitors: Surrogate for Better Response?

A new study in Australia adds to the evolving knowledge on adverse cutaneous effects of pembrolizumab and nivolumab. Could they also indicate better prognosis?

Lichenoid reactions, eczema, and vitiligo were the 3 most prevalent lesions observed among Australian patients treated with a single-agent anti—programmed cell death 1 (PD-1) therapy for metastatic melanoma, according to a new study published in the Journal of the American Academy of Dermatology.1

This prospective and retrospective observational study included 82 patients with unresectable stage IIIC/IV metastatic melanoma who were treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) at or above the FDA-approved dose, between May 1, 2012, and February 1, 2015. Patients previously treated with ipilimumab were included in the study if the interval between ipilimumab and their anti—PD-1 treatment was more than 28 days.

For various reasons, including terminal phase of disease in some patients or patients’ refusal to be evaluated, a formal dermatology review occurred in only 34 of the 82 patients. Nearly 50% of patients developed an anti—PD-1-associated cutaneous adverse event (AE), 17% developed lichenoid reactions and eczema, and 15% developed vitiligo, the authors report. The first lichenoid reactions were estimated to develop within 8.3 months of initiating treatment, and eczema and vitiligo were predicted to develop within 10.3 months of treatment, the authors write, and could develop simultaneously.

Another study published late last year, evaluated the adverse cutaneous events with pembrolizumab and whether they had any bearing on disease progression in those patients.2 The study included 83 patients who were treated with pembrolizumab from March 1, 2011, till May 28, 2014, for melanoma, prostate cancer, lung cancer, and Merkel cell carcinoma. During the median follow-up period of 15 weeks, the authors observed that 42% of patients developed cutaneous AEs, most common being macular papular eruption (29%), pruritus (12%), and hypopigmentation (8%). The most interesting observation was that the patients who developed cutaneous AEs had significantly longer progression-free survival compared with patients who did not. This led the authors to conclude that the development of cutaneous AEs, especially of hypopigmentation in patients with melanoma, could point toward better treatment response

The drug label for pembrolizumab warns against exfoliative dermatitis, pruritis, rash, and vitiligo as the observed skin and tissue disorders in patients with melanoma who were treated with the drug. For nivolumab, the drug label warns against greater incidence of rash and pruritis in more than 10% of patients with melanoma treated with the drug, as compared with chemotherapy. Less than 10% of patients also experienced exfoliative dermatitis, erythema multiforme, vitiligo, and psoriasis.

Being a very new treatment modality, post-marketing data gathered from the real-world can provide a lot of information to both providers and patients on what to expect following treatment—beyond the FDA label.


1. Hwang SJ, Carlos G, Wakade D, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort. J Am Acad Dermatol. 2016;74(3):455-461.e1. doi:10.1016/j.jaad.2015.10.029.

2. Sanlorenzo M, Vujic I, Daud A, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;151(11):1206-1212. doi:10.1001/jamadermatol.2015.1916.

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