背景:Tunlametinib(HL-085)是一种新颖的,高选择性MEK抑制剂在NRAS突变黑色素瘤患者中具有实质性临床活性。这项I期研究评估了替尼联合维罗非尼治疗晚期BRAFV600突变实体瘤患者的安全性和初步疗效。
方法:纳入确诊为晚期BRAFV600突变实体瘤的患者,这些患者在标准治疗中进展或表现出不耐受或没有可用的标准治疗,并接受替尼联合维罗非尼治疗。该研究由剂量递增阶段和剂量扩大阶段组成。这项研究的主要终点是安全性,推荐的II期剂量(RP2D),和初步疗效。
结果:从2018年8月17日至2022年4月19日,纳入72例患者。没有发生剂量限制性毒性,未达到最大耐受剂量。BRAFV600突变非小细胞肺癌(NSCLC)患者的RP2D为替尼9mg加维罗非尼720mg,每天两次(投标,bisindie)。直到2023年12月15日的数据截止日期,33名患有可评估疾病的非小细胞肺癌患者,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(95CI,5.6~14.5),中位缓解持续时间(DoR)为11.3个月(95CI,6.8-NE).在RP2D,ORR为60.0%(9/15;95%CI,32.3-83.7),中位PFS为10.5个月(95CI,5.6-NE),中位DoR为11.3个月(95CI,3.9-NE).在24例具有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例患者均有治疗相关不良事件(TRAEs),最常见的3-4级TRAE是贫血(n=13,18.1%)和血肌酸磷酸激酶升高(n=10,13.9%)。Tunlametinib迅速吸收,Tmax为0.5-1h。Vemurafeinib不影响系统暴露,反之亦然。表明该组合没有药物-药物相互作用。
结论:Tunlametinib(HL-085)联合vemurafenib在BRAFV600突变实体瘤患者中具有良好的安全性,并显示有希望的抗肿瘤活性。NSCLC的RP2D为替尼9mgBID加维非替尼720mgBID。
背景:ClinicalTrials.gov,NCT03781219。
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 Tmax 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.
BACKGROUND: ClinicalTrials.gov, NCT03781219.