A Phase II Study of Efficacy and Safety of the MEK Inhibitor Tunlametinib in Patients with Advanced NRAS-mutant Melanoma

Background: NRAS -mutant melanoma is an aggressive subtype with poor prognosis; however, there is no approved targeted therapy to date worldwide. Methods: We conducted a multicenter, single -arm, phase II, pivotal registrational study that evaluated the efficacy and safety of the MEK inhibitor tunlametinib in patients with unresectable, stage III/IV, NRAS-mutant melanoma (NCT05217303). The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response(DOR), overall survival (OS) and safety. Findings: Between November 2, 2020 and February 11, 2022, a total of 100 patients were enrolled. All ( n = 100) patients received at least one dose of tunlametinib (safety analysis set [SAS]) and 95 had central laboratory-confirmed NRAS mutations (full analysis set [FAS]). In the FAS, NRAS mutations were observed at Q61 (78.9%), G12 (15.8%) and G13 (5.3%). The IRRC-assessed ORR was 35.8%, with a median DOR of 6.1 months. The median PFS was 4.2 months, DCR was 72.6% and median OS was 13.7 months. Subgroup analysis showed that in patients who had previously received immunotherapy, the ORR was 40.6%. No treatment -related deaths occurred. Interpretation: Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS -mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.