Weng Cheng-Di, Liu Ke-Jun, Jin Shi, Su Jun-Wei, Yao Yi-Hui, Zhou Cheng-Zhi, Li Yu-Fa, Chen Ze-Xin, Chen Hua-Jun, Li Yan-Ying, Tang Ke-Jing, Yang Jin-Ji
Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Transl Lung Cancer Res. 2024 Oct 31;13(10):2538-2548. doi: 10.21037/tlcr-24-358. Epub 2024 Oct 28.
The B-Raf proto-oncogene, serine/threonine kinase () V600E mutation is responsible for approximately 3% of acquired resistance mechanisms to epidermal growth factor receptor ()-tyrosine kinase inhibitors (TKIs) in advanced -mutant non-small cell lung cancer (NSCLC). This study investigated the efficacy and safety of a triple-targeted therapy combining EGFR/BRAF/mitogen-activated protein kinase kinase (MEK) inhibitors of dabrafenib, trametinib, and osimertinib in NSCLC patients with acquired V600E mutation after EGFR-TKI treatment.
A multi-center retrospective review of medical records was performed to analyze -mutated advanced Chinese NSCLC patients who acquired the V600E mutation following EGFR-TKI treatment. All patients subsequently received dabrafenib, trametinib, and osimertinib. The clinical characteristics, progression-free survival (PFS), and adverse events (AEs) were documented. The drug response of patient-derived organoids (PDOs) was observed. Next-generation sequencing (NGS) was performed upon progression to triple-targeted therapy.
Thirteen patients with V600E mutations were included. Following triple-targeted therapy, the corresponding objective response rate and disease control rate were 61.5% and 92.3%, respectively. The median PFS was 13.5 months (95% confidence interval: 6.6-20.4). PDOs derived from one patient's tumor sample were established, revealing that the triple-targeted therapy had a significantly lower half-maximal inhibitory concentration (IC) value compared to other regimens. The tumor growth inhibitory rate was 99.36% for dabrafenib, trametinib, and osimertinib; 99.25% for osimertinib plus vemurafenib; 98.92% for osimertinib, encorafenib, and cetuximab; and 62.83% for pemetrexed plus carboplatin. NGS analysis identified major resistance mechanisms following the triple-targeted therapy, including the -dependent pathway, and V600E-dependent pathway, and an off-target mechanism.
EGFR/BRAF/MEK triple-targeted therapy is an effective and safe approach for treating -mutated NSCLC patients resistant to EGFR-TKIs with acquired V600E mutations.
B-Raf原癌基因丝氨酸/苏氨酸激酶（）V600E突变约占晚期突变型非小细胞肺癌（NSCLC）中表皮生长因子受体（）-酪氨酸激酶抑制剂（TKIs）获得性耐药机制的3%。本研究调查了达拉非尼、曲美替尼和奥希替尼这三种EGFR/BRAF/丝裂原活化蛋白激酶激酶（MEK）抑制剂联合治疗EGFR-TKI治疗后出现获得性V600E突变的NSCLC患者的疗效和安全性。
对病历进行多中心回顾性分析，以分析EGFR-TKI治疗后出现V600E突变的晚期中国突变型NSCLC患者。所有患者随后接受了达拉非尼、曲美替尼和奥希替尼治疗。记录临床特征、无进展生存期（PFS）和不良事件（AEs）。观察患者来源类器官（PDOs）的药物反应。在三靶点治疗进展时进行二代测序（NGS）。
纳入13例V600E突变患者。三靶点治疗后，相应的客观缓解率和疾病控制率分别为61.5%和92.3%。中位PFS为13.5个月（95%置信区间：6.6-20.4）。建立了来自一名患者肿瘤样本的PDOs，显示三靶点治疗的半数最大抑制浓度（IC）值明显低于其他方案。达拉非尼、曲美替尼和奥希替尼的肿瘤生长抑制率为99.36%；奥希替尼联合维莫非尼为99.25%；奥希替尼、恩考芬尼和西妥昔单抗为98.92%；培美曲塞联合卡铂为62.83%。NGS分析确定了三靶点治疗后的主要耐药机制，包括依赖途径、和V600E依赖途径以及脱靶机制。
EGFR/BRAF/MEK三靶点治疗是治疗对EGFR-TKIs耐药且出现获得性V600E突变的突变型NSCLC患者的一种有效且安全的方法。
