Dong Xiaorong, Li Xingya, Chen Jianhua, Ma Shenglin, Mu Deguang, Hu Jie, Lu Shun
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
JTO Clin Res Rep. 2022 Dec 13;4(2):100449. doi: 10.1016/j.jtocrr.2022.100449. eCollection 2023 Feb.
INTRODUCTION: c-MET is an important therapeutic target for various cancers; however, the People's Republic of China currently retails only one specific c-MET inhibitor. Our preclinical study has revealed the high selectivity of HS-10241 to suppress c-MET. This phase 1 study aims to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the selective c-MET inhibitor (HS-10241) in patients with advanced solid tumors. METHODS: Patients with locally advanced or metastatic solid tumors orally received a single or multiple dose of HS-10241 once daily or twice daily for 21 consecutive days, which included the following six regimens: 100 mg once daily, 200 mg once daily, 400 mg once daily, 600 mg once daily, 200 mg twice daily, and 300 mg twice daily. The treatment continued until disease progression, unacceptable toxicity, or treatment termination. The primary end point was the incidence of dose-limiting toxicity and maximal tolerated dose (MTD). Secondary end points included safety, tolerability, pharmacokinetics, and pharmacodynamics. RESULTS: A total of 27 patients with advanced NSCLC received HS-10241, and dose-limiting toxicity was observed in three patients after 600 mg once-daily HS-10241 treatment. For once-daily dosing, MTD was 400 mg, and for twice-daily dosing, the maximal safe escalated dose was 300 mg, and MTD was not reached. Nausea (48.1%, 13 of 27), fatigue (37.0%, 10 of 27), and anemia (33.3%, 9 of 27) are the three most frequent treatment-emergent adverse events. At 400 mg once daily, C was 5076 ng/mL and steady state area under the curve was 39,998 h × ng/mL. Patients (n = 5) with positive MET ( exon 14-skipping, amplified, and MET immunohistochemistry 3+) had confirmed partial responses (n = 1) or stable disease (n = 3), with a disease control rate of 80.0%. CONCLUSIONS: The selective c-MET inhibitor HS-10241 was well tolerated and had clinical activity in advanced NSCLC, especially in patients with positive MET. Furthermore, this study expounds on the therapeutic potential of HS-10241 in patients with cancer.
引言：c-MET是多种癌症的重要治疗靶点；然而，中华人民共和国目前仅零售一种特定的c-MET抑制剂。我们的临床前研究已揭示HS-10241对抑制c-MET具有高选择性。这项1期研究旨在评估选择性c-MET抑制剂（HS-10241）在晚期实体瘤患者中的安全性、耐受性、药代动力学和抗肿瘤活性。 方法：局部晚期或转移性实体瘤患者连续21天每天口服一次或多次HS-10241，每日一次或两次，包括以下六种给药方案：每日一次100mg、每日一次200mg、每日一次400mg、每日一次600mg、每日两次200mg和每日两次300mg。治疗持续至疾病进展、出现不可接受的毒性或治疗终止。主要终点是剂量限制性毒性的发生率和最大耐受剂量（MTD）。次要终点包括安全性、耐受性、药代动力学和药效学。 结果：共有27例晚期非小细胞肺癌患者接受了HS-10241治疗，在每日一次600mg HS-10241治疗后，3例患者观察到剂量限制性毒性。对于每日一次给药，MTD为400mg；对于每日两次给药，最大安全递增剂量为300mg，未达到MTD。恶心（48.1%，27例中的13例）、疲劳（37.0%，27例中的10例）和贫血（33.3%，27例中的9例）是三种最常见的治疗中出现的不良事件。每日一次400mg时，C为5076ng/mL，曲线下稳态面积为39998h×ng/mL。MET阳性（外显子14跳跃、扩增和MET免疫组化3+）的患者（n = 5）有确认的部分缓解（n = 1）或疾病稳定（n = 3），疾病控制率为80.0%。 结论：选择性c-MET抑制剂HS-10241耐受性良好，在晚期非小细胞肺癌中具有临床活性，尤其是在MET阳性患者中。此外，本研究阐述了HS-10241在癌症患者中的治疗潜力。
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