Real-World Cutaneous Immune-Related Adverse Events of Immunotherapy in Melanoma: A Systematic Review and Meta-Analysis

Dermatol Ther (Heidelb) (2026) 16:2803–2827 https://doi.org/10.1007/s13555-026-01780-4 SYSTEMATIC REVIEW Real‑World Cutaneous Immune‑Related Adverse Events of Immunotherapy in Melanoma: A Systematic Review and Meta‑Analysis Karolina Zarańska · Grażyna Kamińska‑Winciorek · Alexander Jorge Cortez · Grażyna Wąsik · Maksymilian Gajda Received: March 5, 2026 / Accepted: April 24, 2026 / Published online: May 6, 2026 © The Author(s) 2026 ABSTRACT Introduction: Dermatologic toxicities represent a broad and heterogeneous group of immunerelated adverse events (irAEs) in patients with melanoma treated with immunotherapy, ranging from mild, transient, and self-limiting reactions to severe and potentially life-threatening condi‑ tions. Certain dermatologic toxicities have been Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s13555-026-01780-4. K. Zarańska (*) · G. Kamińska‑Winciorek Students and Young Doctors Research Group, Department of Bone Marrow Transplantation and Oncohematology, Maria SklodowskaCurie National Research Institute of Oncology, 44‑102 Gliwice, Poland e-mail: K. Zarańska · G. Wąsik Clinical Department of Dermatology, Provincial Hospital, 45‑064 Opole, Poland G. Kamińska‑Winciorek Skin Cancer and Melanoma Team, Maria Sklodowska-Curie National Research Institute of Oncology, 44‑102 Gliwice, Poland A. J. Cortez Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, 44‑102 Gliwice, Poland shown to reflect immune system activation and may influence decisions on treatment continua‑ tion. The objective of this study was to compre‑ hensively analyse real-world evidence in order to characterise the frequency, time to onset, and spectrum of dermatologic toxicities in patients with melanoma treated with immunotherapy. Materials and Methods: A systematic litera‑ ture search was conducted in the PubMed and EBSCO (MEDLINE Complete) databases to iden‑ tify relevant reports published between January 2014 and December 2024. Case reports and let‑ ters describing skin toxicities in adult patients with melanoma undergoing immunotherapy were included. Results: A total of 18 patients with melanoma who had experienced dermatologic immunerelated adverse events (d-irAEs) were identified. Breslow thickness ranged from 0.85 to 5.1 mm. The most frequently administered treatment A. J. Cortez Digital Medicine Center, Maria SklodowskaCurie National Research Institute of Oncology, 44‑102 Gliwice, Poland M. Gajda Outpatient Chemotherapy Department, Maria Sklodowska-Curie National Research Institute of Oncology, 44‑102 Gliwice, Poland M. Gajda Department of Epidemiology, School of Medicine in Katowice, Medical University of Silesia, 40‑752 Katowice, Poland Vol.:(0123456789) 2804 was anti-PD-1 monotherapy. All reported cases involved metastatic disease (18/18, 100%; 95% CI 81.47–100%). Autoimmune bullous disorders were the most common toxicities (27.8%; 95% CI 9.69– 53.48%). The median time to onset was 14 weeks (IQR 23.5 weeks; Q1 3.75 weeks; Q3 27.3 weeks). Disease progression or patient death occurred in 12 of 18 cases (66.7%; 95% CI 40.99–86.66%). Conclusion: The increasing prevalence of immunotherapy is accompanied by a paucity of real-world data, particularly with regard to mild-to-moderate skin toxicities. This underre‑ porting emphasises the necessity for systematic documentation to more accurately define the true clinical burden of these events and to pro‑ vide more personalised management strategies for patients with melanoma. Keywords: Skin toxicity; Immunotherapy; Melanoma; Meta-analysis; Systematic review Key Summary Points Dermatologic immune-related adverse events (d-irAEs) in patients with melanoma treated with immune checkpoint inhibitors encompass a broad and heterogeneous spectrum, ranging from mild, self-limiting eruptions to rare, poten‑ tially life-threatening dermatologic conditions. The onset and severity of skin toxicities exhibit significant variability, with the poten‑ tial to occur at any stage of treatment. This underscores the necessity for continuous der‑ matological surveillance, with regular assess‑ ment by a dermatologist during immunother‑ apy. A multidisciplinary approach, integrating both dermatological and oncological exper‑ tise, is fundamental for the early detection and appropriate management of skin toxicities. Real-world d-irAEs, particularly mild-tomoderate manifestations, remain markedly underreported despite widespread immuno‑ therapy use. A systematic approach to reporting real-world d-irAEs is crucial to enhance the personalised management of patients. Dermatol Ther (Heidelb) (2026) 16:2803–2827 INTRODUCTION The incidence of malignant melanoma increases with age, with the highest prevalence observed among fair-skinned older populations with a history of excessive ultraviolet (UV) radiation exposure [1, 2]. Additionally, key risk factors for melanoma development include a high number of benign melanocytic nevi, the presence of atypical nevi, multiple solar lentigi‑ nes, significant sun-induced skin damage, and a family history of melanoma, with mutation in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene being the most commonly identified, accounting for up to 40% of heredi‑ tary cases [2, 3]. Arnold et al. predict that the global burden of melanoma will increase by 50%, reach‑ ing 510,000 new cases by 2040, compared to 325,000 new cases in 2020. Furthermore, the number of melanoma-related deaths is expected to rise by 68% to 96,000 by 2040, compared to 57,000 in 2020 [1]. Genetic alterations play a critical role in mel‑ anoma pathogenesis, with activating mutations in the BRAF gene detected in approximately 40–50% of cases. Among these, the V600E var‑ iant is the most prevalent, accounting for roughly 80% of BRAF mutations [4]. Since 2011, immune checkpoint inhibitors (ICIs) have become a cornerstone in the treat‑ ment of advanced melanoma, representing the first class of therapies approved by the US Food and Drug Administration (FDA) for this indica‑ tion [5]. These agents enhance the T cell-medi‑ ated antitumour response by targeting immune checkpoint proteins, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death receptor 1 (PD-1), and programmed death-ligand 1 (PD-L1) [6, 7]. Recent studies have confirmed the efficacy of ICIs in neoadjuvant, adjuvant, and metastatic melanoma treatment settings [8]. Ipilimumab (anti-CTLA-4) was the first ICI evaluated in patients with completely resected stage III melanoma in a randomised phase III trial (EORTC 18071) [9]. The trial demonstrated significant improvements in both recurrencefree survival (RFS) and overall survival (OS) Dermatol Ther (Heidelb) (2026) 16:2803–2827 compared with the placebo group, resulting in FDA approval of ipilimumab in 2015 [9]. In the CheckMate 238 trial, a randomised phase III study, nivolumab (anti-PD- (...truncated)