Cutaneous adverse events of anti-programmed death 1 antibodies combined with anti-cytotoxic T-lymphocyte-associated protein 4 therapy use in patients with metastatic melanoma

Abstract

To date, cutaneous toxicities of combination therapies of anti-programmed death-1 (anti-PD1) and ipilimumab are poorly described. Understanding cutaneous presentations will aid clinicians with early diagnoses and treatments. We aim to describe and compare the cutaneous toxicities between the combination therapies and anti-PD1 monotherapy. This is a cohort study comparing previously published data on 82 patients with metastatic melanoma on anti-PD1 monotherapy, with a new group of 25 patients with metastatic melanoma receiving combined ipilimumab and pembrolizumab between January 2015 to February 2016. A single institution, internal referrals were received from medical oncology teams from May 2012 to February 2015 for the anti-PD1 monotherapy group and from January 2015 to February 2016 for combination group. All patients who were treated with either anti-PD1 therapy or combination therapies during the timeframe within the institution were included in the study. Kaplan–Meier curves were used to illustrate the time taken to develop cutaneous toxicities in the monotherapy and combination groups. Of the 25 patients, 88% developed new cutaneous lesions since the treatment. Immune-related lesions; lichenoid reaction (64%) and vitiligo (28%) were the most frequent. The incidence of lichenoid reaction increased rapidly in the early phase of treatment. Approximately one-third developed their first lichenoid reaction within 12 days of commencing treatment in combination group compared to 14 months in the anti-PD1 monotherapy. The rate of incidence of vitiligo was comparable in both groups. There was no statistical significance in the development of cutaneous toxicities and the treatment response between the two groups. The time taken to develop immune-related cutaneous toxicities was shorter for those on combination therapy versus anti-PD1 monotherapy.

Melanoma and Vitiligo: In Good Company

“…Leukoderma is an adverse effect of melanoma immunotherapy with check-point inhibitors (Figure 2), with a reported incidence ranging from 3.4% to 28% and a mean onset delay of 30 weeks after therapy initiation [64][65][66][67]. However, even if skin depigmentation is classified as a grade 2 irAE, its appearance does not require therapy discontinuation and could not always be reported.…”

Cutaneous Adverse Events of Targeted Therapies and Immune-Checkpoint Inhibitors in Patients with Melanoma

“…According to recent studies, cuAEs are observed in 70%-88% of the patients, 4,5,38 most commonly non-specific rash, pruritus, lichenoid reactions and vitiligo. 47 They appear earlier and develop more rapidly compared to anti-PD1 monotherapy. 47 It is hypothesized that ipilimumab accelerates the lymphocytic damage to peripheral tissues, thereby causing cutaneous eruptions earlier.…”

Targeting the PD-1/PD-L1 Axis in Human Vitiligo

“…PD-1-targeting monoclonal antibodies have been approved for clinical use and are currently among the first-line treatment options for advanced melanoma patients and many other cancers (28,29). In a fraction of melanoma patients (ranging from 3.4 to 28%), vitiligo-like depigmentation (or melanoma-associated leukoderma) occurs as an adverse effect of immune checkpoint inhibition, indicating the breaking of tolerance to melanocytic self-antigens (30,31). Nevertheless, skin depigmentation has now been reported in anti-PD-1/PD-L1 treated patients with other metastatic cancers as well (32)(33)(34)(35)(36)(37).…”