Actionable Gene Alterations Identified in Patients With Malignant Melanoma by Targeted Sequencing in Japan

Precision medicine plays an important role in the treatment of patients with advanced melanoma. Despite its high incidence in White patients, advanced melanoma is rare in Asian countries, hampering prospective clinical trials targeting the Asian population. This retrospective study aimed to elucidate the real-world molecular diagnoses and outcomes of Japanese patients with melanoma using comprehensive genome profiling (CGP).

Patients with melanoma who completed standard anticancer medical treatments (including those expected to complete the treatments) underwent CGP, which is covered by the National Health Insurance. We analyzed the results and clinical annotations of 569 patients registered before August 2023 in a national database.

Skin, mucosal, and uveal melanomas accounted for 64%, 28%, and 7% of cases, respectively. Patients with BRAF, NRAS, NF1, and KIT variants represented 25%, 20%, 17%, and 17%, respectively. Eighty-two percent of BRAF, 97% of NRAS, 69% of NF1, and 54% of KIT were actionable alterations (ie, BRAF classes I, II, and III, NRAS Q61, G12, G13, NF1 loss-of-function, KIT gain-of-function variants). BRAF V600E/K variants occurred in 22% of skin and 2% of mucosal melanomas, but not in uveal melanomas. The mean tumor mutation burden in cutaneous melanomas was 4.2 variants/Mb. Patients previously treated with BRAF-targeted therapy harbored amplifications of BRAF and cell cycle genes more frequently than therapy-naive patients. Thirty-six patients (6.3%) were treated following the molecular tumor board (MTB) recommendations.

Actionable gene alterations in BRAF, NRAS, NF1, and KIT are common in Japanese patients with melanoma. However, few patients were treated according to the MTB recommendations, suggesting that there is an unmet need to increase accessibility to gene-matched clinical trials in Japan.