Binimetinib 和羟氯喹治疗晚期 KRAS 突变型非小细胞肺癌患者的 II 期开放标签试验。
A Phase II Open-Label Trial of Binimetinib and Hydroxychloroquine in Patients With Advanced KRAS-Mutant Non-Small Cell Lung Cancer.
机构信息
Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
Department of Internal Medicine, Lankenau Medical Center, Wynnewood, PA, USA.
出版信息
Oncologist. 2023 Jul 5;28(7):644-e564. doi: 10.1093/oncolo/oyad106.
BACKGROUND
In RAS-mutant tumors, combined MEK and autophagy inhibition using chloroquine demonstrated synthetic lethality in preclinical studies. This phase II trial evaluated the safety and activity of the MEK inhibitor binimetinib combined with hydroxychloroquine (HCQ) in patients with advanced KRAS-mutant non-small cell lung cancer (NSCLC).
METHODS
Eligibility criteria included KRAS-mutant NSCLC, progression after first-line therapy, ECOG PS 0-1, and adequate end-organ function. Binimetinib 45 mg was administered orally (p.o.) bid with HCQ 400 mg p.o. bid. The primary endpoint was objective response rate (ORR). A Simon's 2-stage phase II clinical trial design was used, with an α error of 5% and a power β of 80%, anticipating an ORR of 30% to proceed to the 2-stage expansion.
RESULTS
Between April 2021 and January 2022, 9 patients were enrolled to stage I: median age 64 years, 44.4% females, 78% smokers. The best response was stable disease in one patient (11.1%). The median progression free survival (PFS) was 1.9 months, and median overall survival (OS) was 5.3 months. Overall, 5 patients (55.6%) developed a grade 3 adverse event (AE). The most common grade 3 toxicity was rash (33%). Pre-specified criteria for stopping the trial early due to lack of efficacy were met.
CONCLUSION
The combination of B + HCQ in second- or later-line treatment of patients with advanced KRAS-mutant NSCLC did not show significant antitumor activity. (ClinicalTrials.gov Identifier: NCT04735068).
背景
在 RAS 突变肿瘤中，使用氯喹联合 MEK 和自噬抑制在临床前研究中显示出合成致死性。这项 II 期试验评估了 MEK 抑制剂比美替尼联合羟氯喹 (HCQ) 在晚期 KRAS 突变非小细胞肺癌 (NSCLC) 患者中的安全性和活性。
方法
入选标准包括 KRAS 突变 NSCLC、一线治疗后进展、ECOG PS 0-1 和足够的终末器官功能。比美替尼 45 mg 口服（po）bid，HCQ 400 mg po bid。主要终点是客观缓解率（ORR）。采用西蒙两阶段 II 期临床试验设计，α 错误为 5%，β 功率为 80%，预计 ORR 为 30%以进行两阶段扩展。
结果
2021 年 4 月至 2022 年 1 月期间，9 名患者入组 I 期：中位年龄 64 岁，44.4%为女性，78%为吸烟者。最佳缓解为 1 例患者（11.1%）的疾病稳定。中位无进展生存期（PFS）为 1.9 个月，中位总生存期（OS）为 5.3 个月。总体而言，5 名患者（55.6%）发生 3 级不良事件（AE）。最常见的 3 级毒性是皮疹（33%）。由于缺乏疗效，提前规定了提前终止试验的标准。
结论
B + HCQ 联合用于晚期 KRAS 突变 NSCLC 的二线或后线治疗并未显示出显著的抗肿瘤活性。（临床试验注册编号：NCT04735068）。
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