European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2024

Abstract

A unique collaboration of multi-disciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cutaneous melanoma diagnosis and treatment, based on systematic literature reviews and the experts' experience. Cutaneous melanomas are excised with one to two-centimeter safety margins. For a correct stage classification and treatment decision, a sentinel lymph node biopsy shall be offered in patients with tumor thickness ≥ 1.0 mm or ≥ 0.8 mm with additional histological risk factors, although there is as yet no clear survival benefit for this approach. Therapeutic decisions should be primarily made by an interdisciplinary oncology team ("Tumor Board"). Adjuvant therapies can be proposed in completely resected stage IIB-IV. In stage II only PD-1 inhibitors are approved. In stage III anti-PD-1 therapy or dabrafenib plus trametinib for patients with BRAFV600 mutated melanoma can be discussed. In resected stage IV, nivolumab can be offered, as well as ipilimumab and nivolumab, in selected, high-risk patients. In patients with clinically detected macroscopic, resectable disease, neoadjuvant therapy with ipilimumab plus nivolumab followed complete surgical resection and adjuvant therapy according to pathological response and BRAF status can be offered. Neoadjuvant therapy with pembrolizumab followed by complete surgical resection and adjuvant pembrolizumab is also recommended. For patients with disease recurrence after (neo) adjuvant therapy, further treatment should consider the type of (neo) adjuvant therapy received as well as the time of recurrence, i.e., on or off therapy. In patients with irresectable stage III/IV disease systemic treatment is always indicated. For first line treatment PD-1 antibodies alone or in combination with CTLA-4 or LAG-3 antibodies shall be considered. In stage IV melanoma with a BRAFV600 mutation, first-line therapy with BRAF/MEK inhibitors can be offered as an alternative to immunotherapy, in selected cases. In patients with primary resistance to immunotherapy and harboring a BRAFV600 mutation, this therapy shall be offered as second line. Other second line therapies include therapy with tumor infiltrating lymphocytes and combinations of immune checkpoint inhibitors not used in first line. This guideline is valid until the end of 2026.

Keywords: Adjuvant therapy; BRAF and MEK inhibitors; Brain metastases; Cutaneous melanoma; Immune checkpoint inhibitors; Neoadjuvant therapy; Targeted therapy.