Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Research Institute, Beijing, China.
Comprehensive Cancer Center (word B7) of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Eur J Cancer. 2024 May;202:114008. doi: 10.1016/j.ejca.2024.114008. Epub 2024 Mar 11.
NRAS-mutant melanoma is an aggressive subtype with poor prognosis; however, there is no approved targeted therapy to date worldwide.
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.
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.
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.
NRAS 突变型黑色素瘤是一种侵袭性亚型，预后不良；然而，迄今为止，全球范围内尚无批准的靶向治疗药物。
我们开展了一项多中心、单臂、Ⅱ期关键性注册研究，评估 MEK 抑制剂曲美替尼在不可切除的 III/IV 期NRAS 突变型黑色素瘤患者中的疗效和安全性（NCT05217303）。主要终点为独立影像学审查委员会（IRRC）根据实体瘤反应评估标准（RECIST）v1.1 评估的客观缓解率（ORR）。次要终点包括无进展生存期（PFS）、疾病控制率（DCR）、缓解持续时间（DOR）、总生存期（OS）和安全性。
2020 年 11 月 2 日至 2022 年 2 月 11 日期间，共入组 100 例患者。所有（n=100）患者均至少接受了一次曲美替尼治疗（安全性分析集 [SAS]），95 例患者的 NRAS 突变经中心实验室确认（全分析集 [FAS]）。在 FAS 中，NRAS 突变发生在 Q61（78.9%）、G12（15.8%）和 G13（5.3%）。IRRC 评估的 ORR 为 35.8%，中位 DOR 为 6.1 个月。中位 PFS 为 4.2 个月，DCR 为 72.6%，中位 OS 为 13.7 个月。亚组分析显示，在先前接受过免疫治疗的患者中，ORR 为 40.6%。无治疗相关死亡事件发生。
曲美替尼在晚期 NRAS 突变型黑色素瘤患者中显示出有前景的抗肿瘤活性和可管理的安全性特征，包括那些先前曾接受过免疫治疗的患者。这些发现需要在随机临床试验中进一步验证。
