Shi Yuankai, Han Xiaohong, Zhao Qian, Zheng YuLong, Chen Jianhua, Yu Xinmin, Fang Jian, Liu Yutao, Huang Dingzhi, Liu Tianshu, Shen Hong, Luo Suxia, Yu Hongsheng, Cao Yu, Zhang Xi, Hu Pei
Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People's Republic of China.
Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1, Shuaifuyuan, Dongcheng District, Beijing, 100730, People's Republic of China.
Exp Hematol Oncol. 2024 Jun 12;13(1):60. doi: 10.1186/s40164-024-00528-0.
BACKGROUND: Tunlametinib (HL-085) is a novel, highly selective MEK inhibitor with substantial clinical activities in patients with NRAS-mutant melanoma. This phase I study evaluated the safety and preliminary efficacy of tunlametinib plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors. METHODS: Patients with confirmed advanced BRAF V600-mutant solid tumors who had progressed on or shown intolerance or no available standard therapies were enrolled and received tunlametinib plus vemurafenib. This study consisted of a dose-escalation phase and a dose-expansion phase. Primary end points of this study were safety, the recommended phase II dose (RP2D), and preliminary efficacy. RESULTS: From August 17, 2018 to April 19, 2022, 72 patients were enrolled. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. The RP2D for BRAF V600-mutant non-small cell lung cancer (NSCLC) patients was tunlametinib 9 mg plus vemurafenib 720 mg, twice daily (BID, bis in die). Until the data cut-off date of December 15, 2023, of 33 NSCLC patients with evaluable disease, the objective response rate (ORR) was 60.6% (20/33; 95% confidence interval [CI], 42.1-77.1), the median progression free survival (PFS) was 10.5 months (95%CI, 5.6-14.5) and median duration of response (DoR) was 11.3 months (95%CI, 6.8-NE). At the RP2D, ORR was 60.0% (9/15; 95% CI, 32.3-83.7), the median PFS was 10.5 months (95%CI, 5.6 -NE) and median DoR was 11.3 months (95%CI, 3.9-NE). Of 24 colorectal cancer patients with evaluable disease, the ORR was 25.0% (6/24; 95% CI, 5.6-NE). All 72 patients had treatment-related adverse events (TRAEs), and the most common grade 3-4 TRAEs were anemia (n = 13, 18.1%) and blood creatine phosphokinase increased (n = 10, 13.9%). Tunlametinib was absorbed rapidly with T of 0.5-1 h. Vemurafeinib did not influence the system exposure of tunlametinib and vice versa, indicating no drug-drug interaction for this combination. CONCLUSIONS: Tunlametinib (HL-085) plus vemurafenib had a favorable safety profile and showed promising antitumor activity in patients with BRAF V600-mutant solid tumors. The RP2D for NSCLC was tunlametinib 9 mg BID plus vemurafeinib 720 mg BID. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03781219.
背景：图拉替尼（HL-085）是一种新型、高度选择性的MEK抑制剂，对NRAS突变型黑色素瘤患者具有显著的临床活性。这项I期研究评估了图拉替尼联合维莫非尼治疗晚期BRAF V600突变实体瘤患者的安全性和初步疗效。 方法：招募确诊为晚期BRAF V600突变实体瘤且疾病进展、不耐受或无可用标准治疗方案的患者，给予图拉替尼联合维莫非尼治疗。本研究包括剂量递增阶段和剂量扩展阶段。本研究的主要终点为安全性、推荐的II期剂量（RP2D）和初步疗效。 结果：2018年8月17日至2022年4月19日，共入组72例患者。未发生剂量限制性毒性，未达到最大耐受剂量。BRAF V600突变非小细胞肺癌（NSCLC）患者的RP2D为图拉替尼9mg联合维莫非尼720mg，每日两次（BID，bis in die）。截至2023年12月15日的数据截止日期，33例可评估疾病的NSCLC患者中，客观缓解率（ORR）为60.6%（20/33；95%置信区间[CI]，42.1-77.1），中位无进展生存期（PFS）为10.5个月（95%CI，5.6-14.5），中位缓解持续时间（DoR）为11.3个月（95%CI，6.8-NE）。在RP2D剂量下，ORR为60.0%（9/15；95%CI，32.3-83.7），中位PFS为10.5个月（95%CI，5.6-NE），中位DoR为11.3个月（95%CI，3.9-NE）。24例可评估疾病的结直肠癌患者中，ORR为25.0%（6/24；95%CI，5.6-NE）。所有72例患者均发生治疗相关不良事件（TRAEs），最常见的3-4级TRAEs为贫血（n = 13，18.1%）和血肌酸磷酸激酶升高（n = 10，13.9%）。图拉替尼吸收迅速，达峰时间为0.5-1小时。维莫非尼不影响图拉替尼的系统暴露，反之亦然，表明该联合用药不存在药物相互作用。 结论：图拉替尼（HL-085）联合维莫非尼具有良好的安全性，在BRAF V600突变实体瘤患者中显示出有前景的抗肿瘤活性。NSCLC的RP2D为图拉替尼9mg每日两次联合维莫非尼720mg每日两次。 试验注册：ClinicalTrials.gov，NCT03781219。
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