A phase III, open-label, multicenter, randomized controlled trial of tunlametinib versus investigator-selected chemotherapy in patients with advanced NRAS-mutant melanoma who had previously received immunotherapy.

person Xiaoting Wei Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China info_outline Xiaoting Wei, Weizhen Zhang, Meiyu Fang, Zhengyun Zou, Jing Chen, Zhiguo Luo, Hongqi Tian, Zhongwei Jia, Jun Guo, Lu Si

Authors person Xiaoting Wei Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China info_outline Xiaoting Wei, Weizhen Zhang, Meiyu Fang, Zhengyun Zou, Jing Chen, Zhiguo Luo, Hongqi Tian, Zhongwei Jia, Jun Guo, Lu Si Organizations Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China, Department of Melanoma Oncology, The Third People's Hospital of Zhengzhou, Zhengzhou, China, Department of Head and Neck and Rare Oncology, Zhejiang Cancer Hospital, Hangzhou, China, The Comprehensive Cancer Center of Drum-Tower Hospital, Nanjing, China, Union Hospital, Cancer Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China, Shanghai Kechow Pharma, Inc., Shanghai, China, Department of Clinical Research and Development, Shanghai Kechow Pharma, Inc., Shanghai, China, Department of Melanoma and Sarcoma Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China Abstract Disclosures Research Funding Shanghai KeChow Pharma. Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we present the design of phase III randomized controlled study. Methods: This is a multicenter, two-arm, open-label, randomized controlled phase III confirmatory clinical trial to evaluate the efficacy and safety of tunlametinib in comparison with the combination chemotherapy of investigator's choice in advanced NRAS-mutant melanoma patients who had previously received immunotherapy. A total of 165 subjects from about 12 sites in China will be included and randomly assigned to the corresponding treatment group in 2:1 ratio. Two stratification factors before randomization: LDH level and whether have received chemotherapy. The key inclusion criteria included: a) Patients with unresectable stage III or metastatic IV melanoma confirmed by histology or cytology; b) History of immunotherapy failure or could not tolerate immunotherapy; c) Be able to provide NRAS mutation positive test report at baseline and provide sufficient histological specimens for NRAS mutation confirmation by central laboratory. Experimental group subjects will receive continuous administration of tunlametinib 12mg BID, 28 days per cycle. Control group subjects will receive one of the following regimens which according to investigator's choice (paclitaxel plus carboplatin, or temozolomide plus cisplatin, or dacarbazine plus cisplatin) , 28 days per cycle. The two groups will receive continuous therapy until disease progression or intolerable toxicity. The primary endpoint is progression-free survival which assessed by independent radiology review committee. Secondary endpoints included overall survival, objective response rate, disease control rate, duration of response, safety, pharmacokinetics and exposure-response. Exploratory endpoints are to evaluate quality of life between two groups and to development a companion diagnostic kit for NRAS gene mutations detection. This study is currently open for enrollment. Clinical trial information: NCT06008106.

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