Pediatric Melanoma: Emerging Therapies and Ongoing Clinical Trials

Dermatol Ther (Heidelb) https://doi.org/10.1007/s13555-026-01817-8 REVIEW Pediatric Melanoma: Emerging Therapies and Ongoing Clinical Trials Pablo Balado‑Simó · Marc Hernández‑Santacana · Miguel Mansilla‑Polo · Cristina Carrera · Susana Puig Received: April 27, 2026 / Accepted: May 26, 2026 © The Author(s) 2026 ABSTRACT Pediatric melanoma is a rare but clinically dis‑ tinct malignancy, accounting for 1–4% of all melanoma cases. It encompasses unique sub‑ types—Spitzoid melanoma, melanoma arising in congenital melanocytic nevi, and conven‑ tional melanoma—each with specific biological behavior and therapeutic implications. While surgical excision remains the primary treat‑ ment, systemic therapies are often adapted from adult protocols and used off-label, with Pablo Balado-Simó, Marc Hernández-Santacana and Miguel Mansilla-Polo have contributed equally to this work and are considered as first co-authors. P. Balado‑Simó · M. Hernández‑Santacana · C. Carrera · S. Puig (*) Dermatology Department, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain e-mail: M. Mansilla‑Polo Dermatology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain limited pediatric-specific data on efficacy, dos‑ ing, and safety. This narrative review summa‑ rizes current treatment approaches, including the use of immune checkpoint inhibitors and targeted therapies, and highlights outcomes from available prospective and retrospective studies. Furthermore, it reviews ongoing clini‑ cal trials investigating novel strategies such as chimeric antigen receptor (CAR) T-cell therapy, natural killer (NK) cell infusions, Wnt/β-catenin pathway inhibitors, and cancer vaccines. Despite emerging interest, challenges persist due to the rarity of the disease, lack of long-term toxic‑ ity data, and limited biomarker-driven strati‑ fication. Expanding pediatric-focused clinical research, integrating molecular profiling, and addressing developmental and psychosocial needs are essential for advancing care. Ongoing trials may help pave the way for safer and more effective therapies tailored to this vulnerable population. Keywords: Pediatric melanoma; CAYA melanoma; Immunotherapy; Targeted therapy; Clinical trials M. Mansilla‑Polo Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain C. Carrera · S. Puig CIBERER, Instituto de Salud Carlos III, Barcelona, Spain Vol.:(0123456789) Dermatol Ther (Heidelb) Key Summary Points Pediatric melanoma is a rare but distinct malignancy with unique subtypes and clinical features that often delay diagnosis and complicate treatment selection Most systemic therapies are adapted from adult protocols and used off-label, with limited data on efficacy, safety, and long-term outcomes in pediatric populations Emerging strategies under clinical investigation include immune checkpoint inhibitors, BRAF/MEK-targeted therapies, CAR-T cells, NK cell infusions, and β-catenin pathway inhibitors Addressing unmet needs—such as the lack of pediatric-specific trials, validated biomarkers, and psychosocial care—alongside expanding precision medicine and ageadapted protocols, is essential for improving outcomes INTRODUCTION Pediatric melanoma is a rare but increasingly recognized malignancy, accounting for approximately 1–4% of all melanoma cases and 1% of all pediatric malignancies [1, 2]. This percentage is greater in adolescents, where melanoma causes 7.1% of all malignancies in subjects aged 15–19 years [3]. Pediatric melanoma exhibits distinct histologic subtypes, which include three subtypes: Spitz melanoma, melanoma arising in congenital melanocytic nevi (CMN), and conventional melanoma [1, 4]. Each of them has unique biological behaviors and therapeutic implications [4], as well as different dermoscopic characteristics [5]. Diagnostic delays are common due to atypical clinical presentations and a low index of suspicion in children. Pediatric melanomas often present without the classic features— amelanotic, bleeding/bumps, color uniformity, de novo, evolution (ABCDE)—in adults, so alternative algorithms have been proposed to help with detection: the modified ABCDE and color, uniformity, and pop-up (CUP) [6]. Also, Spitzoid lesions often mimic benign Spitz nevi and Spitz melanoma, as these entities are difficult to distinguish without molecular analysis [4]. As a result, those rare cases of real melanomas are diagnosed at advanced stages, impacting prognosis and therapeutic decision-making. The rarity of pediatric melanoma has major therapeutic implications. Very few systemic therapies have been formally evaluated in children, and pediatric-specific approvals, dosing data, and long-term safety information remain limited. Consequently, treatment decisions for high-risk or advanced disease are frequently based on adult melanoma evidence, small pediatric series, compassionate-use experiences, or off-label use of immune checkpoint inhibitors and targeted therapies. Treatment guidelines for pediatric melanoma are largely extrapolated from adult studies, particularly for high-risk and metastatic cases [7, 8]. The cornerstone of therapy remains surgical resection (which is curative in the majority of cases) [8]; however, adjuvant and systemic therapies are often used off-label in pediatric settings with limited data on pharmacokinetics, efficacy, and toxicity. While recent advances in immunotherapy and precision oncology have revolutionized melanoma management in adults, translating these breakthroughs to pediatric patients remains challenging. The scarcity of dedicated clinical trials, the rarity of the disease, and concerns over long-term toxicities in growing children have slowed therapeutic innovation. However, some studies are exploring the role of molecular diagnostics and registries in improving classification and guiding therapy [9]. This narrative review aims to summarize the current treatment landscape of pediatric melanoma, highlight ongoing clinical trials investigating emerging therapies, and discuss future directions that could pave the way for more personalized, effective, and safer interventions in this vulnerable population. In this review, we focus on children and adolescents and, when relevant, on the broader children, adolescents and young adults (CAYA) population, given the rarity of melanoma in Dermatol Ther (Heidelb) younger age groups and the frequent inclusion of adolescents and young adults in available cohorts and clinical trials. For clarity, we refer to “pediatric” as < 18 years and to “CAYA” as patients ≤ 21 years; when evidence comes from trials, including older AYA patients (e.g., up to 30 years), this is explicitly stated. METHODS The objective of this narrative review was to identify, summarize, and critically evaluate the clinical evidence supporting current and emerging therapies for pediatric melanoma, including both approved and offlabel treatments, as well as ongoing clinical trials. This review (...truncated)