Cutaneous Toxicities of Advanced Treatment for Cutaneous Melanoma: A Prospective Study from a Single-Center Institution

Abstract

Background/objectives: The landscape of advanced melanoma treatments has shifted dramatically in recent years. Target therapy and immunotherapy have changed the management of patients with both metastatic (stage IV according to AJCC 8th ed.) and nodal (stage IIB/C and III) disease. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, high-grade or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining a patient's quality of life is of paramount importance.

Methods: We undertook a prospective, monocentric, and descriptive study in Bologna, Italy, including patients referred to the Oncologic Dermatology Unit of IRCCS AOU of Bologna who developed biopsy-proven cutaneous adverse events (AE) under treatment with immunotherapy for cutaneous melanoma with nodal (stage IIB/C, III) and metastatic (stage IV) disease from January 2016 to April 2024.

Results: In 202 identified patients, 75 (37.5%) developed skin AEs. Ipilimumab was causal for 48.1% of skin AEs, followed by nivolumab (37%) and pembrolizumab (31.4%). Recorded types of skin AEs included erythematous rash, vitiligo, alopecia, lichenoid, maculopapular, acneiform, urticarial, psoriasiform, granulomatous, eczematous, and severe cutaneous AEs, such as Erythema multiforme/Stevens-Johnson syndrome and bullous autoimmune dermatoses. Most AEs were low-grade [CTCAE 1-2] (97%) and typically occurred after 10 weeks of treatment.

Conclusions: This study comprehensively describes skin AEs occurring during systemic treatment with ICIs for cutaneous melanoma at a single center.

Keywords: cutaneous toxicity; immunotherapy; ipilimumab; melanoma; nivolumab; pembrolizumab; toxicity.

Figure 1

Cutaneous toxicities related to ICIs in melanoma patients: Vitiligo irAE in a 58-year-old patient with metastatic melanoma (stage IV) treated with anti-PD-1 antibody (nivolumab) (a,b). Flare-up of psoriasis in an 83-year-old patient with metastatic melanoma (stage IV) treated with anti-PD-1 antibody (pembrolizumab) (c,d). Exfoliative dermatitis (NET syndrome) in a 67-year-old patient with stage III melanoma treated with anti-PD-1 antibody (nivolumab). Clinical (e) and dermoscopic (f) presentation of disease. Erosive lichenoid reaction in an 80-year-old patient with metastatic melanoma (stage IV) treated with anti-PD-1 antibody (pembrolizumab) (g,h). Erythematous rash in a 46-year-old patient with stage IIc melanoma treated with anti-PD-1 antibody (nivolumab) (i).

Figure 2

Graphical representation of cutaneous irAEs in our study population with distinction for each ICIs agent (pembrolizumab, nivolumab, ipilimumab, respectively).

Figure 3

Graphical representation of mean time to first onset (weeks) of cutaneous irAEs in our study population.

Figure 4

Graphical representation of mean cumulative duration (weeks) of cutaneous irAEs in our study population.

Figure 5

Graphical representation of severity of cutaneous irAEs in our study population (according to CTCAE v 5.0).

Figure 6

Means and medians for survival time in our study population.

Figure 7

Survival curves of our cohort, displaying patients treated with ICIs for cutaneous melanoma who had been subject to skin irAEs within the first 3 months of therapy vs. patients who had not been subject to it.