Tunlametinib (HL-085) plus vemurafenib in patients with advanced BRAF V600-mutant solid tumors: an open-label, single-arm, multicenter, phase I study.

IF 9.4 1区医学 Q1 HEMATOLOGY Experimental Hematology & Oncology Pub Date : 2024-06-12 DOI:10.1186/s40164-024-00528-0

Yuankai Shi, Xiaohong Han, Qian Zhao, YuLong Zheng, Jianhua Chen, Xinmin Yu, Jian Fang, Yutao Liu, Dingzhi Huang, Tianshu Liu, Hong Shen, Suxia Luo, Hongsheng Yu, Yu Cao, Xi Zhang, Pei Hu

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Abstract

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_max 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.

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Tunlametinib (HL-085) 加维莫非尼治疗晚期 BRAF V600 突变实体瘤患者：一项开放标签、单臂、多中心 I 期研究。

研究背景Tunlametinib（HL-085）是一种新型、高选择性MEK抑制剂，在NRAS突变黑色素瘤患者中具有显著的临床活性。这项I期研究评估了通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：入组确诊的晚期BRAF V600突变实体瘤患者接受了曲拉米替尼联合vemurafenib治疗，这些患者在接受标准疗法后病情有所进展或出现不耐受或无可用疗法。这项研究包括剂量递增阶段和剂量扩大阶段。本研究的主要终点是安全性、II期推荐剂量（RP2D）和初步疗效：从2018年8月17日至2022年4月19日，共有72名患者入组。未出现剂量限制性毒性，也未达到最大耐受剂量。BRAF V600突变非小细胞肺癌（NSCLC）患者的RP2D为曲拉米替尼9毫克加维莫非尼720毫克，每日两次（BID，bis in die）。截至2023年12月15日数据截止日，在33例可评估疾病的NSCLC患者中，客观应答率（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），中位应答持续时间（DoR）为11.3个月（95%CI，6.8-NE）。在 RP2D 阶段，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）。在 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名患者都发生了治疗相关不良事件（TRAE），最常见的3-4级TRAE是贫血（13例，18.1%）和血肌酸磷酸激酶升高（10例，13.9%）。屯拉米替尼吸收迅速，Tmax为0.5-1小时。Vemurafeinib不影响屯拉米替尼的系统暴露，反之亦然，表明该联合用药不存在药物间相互作用：结论：Tunlametinib（HL-085）联合vemurafenib对BRAF V600突变实体瘤患者具有良好的安全性和抗肿瘤活性。治疗 NSCLC 的 RP2D 为 tunlametinib 9 mg BID 加 vemurafeinib 720 mg BID：试验注册：ClinicalTrials.gov，NCT03781219。

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来源期刊

Experimental Hematology & Oncology Medicine-Oncology

CiteScore

12.60

自引率

7.30%

发文量

审稿时长

6 weeks

期刊介绍： Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings. Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.