MET and NF2 alterations confer primary and early resistance to first‐line alectinib treatment in ALK ‐positive non‐small‐cell lung cancer

作者：Jie Hu, Ning Ding, Xiaobo Xu, Yedan Chen, Yong Zhang, Jingwen Liu, Jiebai Zhou, Hairong Bao, Donghui Zhang, Yijun Song, Yang Shao, Yuanlin Song · 发表于：Molecular Oncology · 年份：2025 · DOI：10.1002/1878-0261.70029 · 被引用次数：4 · 研究领域：Lung Cancer Treatments and Mutations、Lung Cancer Research Studies、Cholangiocarcinoma and Gallbladder Cancer Studies

Although first-line alectinib has prolonged survival in ALK-mutated non-small-cell lung cancers (NSCLCs), the response to treatment varies among patients, and the primary/early development of alectinib resistance mechanisms is still not fully understood. Here, we analyzed molecular profiles of 108 alectinib-treated patients (first-line and second-line after crizotinib) with confirmed relapse by targeted sequencing of cancer-related genes. After first-line treatment, off-target MET and NF2 alterations were more frequent than on-target alterations within the first 6 months, causing primary or early resistance. Conversely, on-target alterations became prevalent after 1 year of first-line alectinib treatment and predominantly after second-line. The incidence of acquired resistance also depended on EML4-ALK variants. In variant 1 (v1), off-target alterations were responsible for 50% of resistance cases after first-line alectinib therapy, whereas on-target mutations had no contribution in this subgroup. In variant 3 (v3), on-target alterations resulted in 46% of resistance cases, whereas only 18% were caused by off-target mutations. After second-line treatment, the most common mutations in v1 were L1196M (42%) and G1269A (25%), while G1202R was detected in 45% of v3 tumors. These findings emphasize the importance of stratifying resistance mechanisms to guide tailored treatment for ALK-positive NSCLCs.