Cutaneous Side Effects of PD-1 Inhibitors: A Single-Center Retrospective Study

Abstract

Background: The introduction of immune checkpoint inhibitors (ICIs) opened a new era in cancer immunotherapy. In particular, PD-1 inhibitors have shown remarkable efficacy in various cancers, most notably melanoma. However, the widespread use of immune checkpoint inhibitors comes with the challenge of immune-related adverse events (irAEs), with cutaneous toxicities being the most prevalent.

Methods: A retrospective, single-center study was carried out to investigate the cutaneous side effects in patients diagnosed with melanoma and treated with PD-1 inhibitors (pembrolizumab or nivolumab) at the Department of Dermatology, Venereology, and Oncodermatology, University of Pécs, Hungary. The study included patients with stage III or IV melanoma who received PD-1 inhibitor monotherapy, either for metastatic or adjuvant purposes, from August 2015 to May 2022.

Results: A cohort of 174 patients was examined, with 29% experiencing cutaneous adverse events (cAEs). The most prevalent cutaneous toxicities were vitiligo (n = 18; 27%), maculopapular rash (n = 14; 21%), pruritus (n = 14; 21%), xerostomia (n = 8; 12%), and lichenoid dermatitis (n = 4; 6%). Treatment primarily involved topical corticosteroids and emollients, with a few cases requiring systemic therapy. Notably, the occurrence of dermatologic adverse events was associated with improved progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.026) compared to those without any skin toxicity (p < 0.0001), emphasizing their potential prognostic significance. Our data were not influenced by any well-known prognostic factors of melanoma.

Conclusion: Our study contributes to the growing body of evidence supporting the prognostic value of cutaneous adverse events in patients treated with PD-1 inhibitors. Optimizing treatment strategies while maintaining oncologic therapy is essential, highlighting the role of dermatologists in multidisciplinary cancer care.

Keywords: PD‐1 inhibitor; immune checkpoint inhibitors; immune‐related cutaneous side effect; melanoma; skin toxicity.

FIGURE 1

PD‐1 inhibitor‐induced cutaneous side effects: (a) oral mucosal lichenoid reaction involving the lip, (b) dermoscopic image of oral lichen depicting the Wickham striae, (c) hypopigmentation on the right arm, (d) small, tense bullae, and erosions on the forearm‐suggestive of bullous pemphigoid, and (e) alopecia areata.

FIGURE 2

(a) Multiple erosions and papules on the upper leg in a melanoma patient undergoing PD‐1 inhibitor therapy. (b) Histology shows a moderate peri‐ and intrafollicular mononuclear infiltrate containing eosinophils. The follicle shows mild intercellular edema, and a perivascular inflammatory infiltrate is also evident (HE 11.4×). (c) Eosinophil cells are visible at higher magnification among the lymphocytes (HE 63×). The histologic findings are consistent with early eosinophilic folliculitis.

FIGURE 3

(a) Erosions and crusts on the lips involving oral mucosa. (b) Multiple erythematous papules and macules on the trunk. (c) Histology revealed a normal basket‐weave stratum corneum on the surface. The epidermis shows basal vacuolar degeneration with apoptotic keratinocytes characterized by intensely eosinophilic cytoplasm and pycnotic hyperchromatic nuclei. A mild perivascular lymphohistiocytic infiltrate in the dermis is present with scattered eosinophils (HE 40×).

FIGURE 4

Kaplan–Meier curves of (a) progression‐free survival and (b) overall survival in melanoma patients treated with anti‐PD‐1 therapy compared by the presence and absence of dermatological side effects. (c) Forest plot of Cox proportional hazards model indicating the effect size of different covariates on progression‐free survival and (d) overall survival. The estimated hazard ratio and confidence interval are displayed for each covariate against the reference level alongside the p value.

FIGURE 5

Kaplan–Meier curves of (a) overall survival and (b) progression‐free survival comparing the presence and absence of dermatological side effects, including vitiligo versus non‐vitiligo cases. (c) Kaplan–Meier curve of overall survival according to the development of inflammatory skin disorder. (d) Kaplan–Meier curve of overall survival according to the development of maculopapular rash.

FIGURE 6

(a) Kaplan Meier curves showing the overall survival of metastatic and adjuvant setting patients comparing the presence and absence of dermatological side effects. (b–d) Bar charts showing the ratio of metastatic and adjuvant setting patients. (b) All patients with cutaneous and non‐cutaneous side effects. (c) Non‐cutaneous side effects, categorized by grade. (d) Cutaneous side effects, categorized by grade. Fisher's exact test on count data between adjuvant and metastatic groups is not significant in either comparison.