Zhonghua Yi Xue Za Zhi. 2025 Dec 2;105(44):4048-4055. doi: 10.3760/cma.j.cn112137-20250924-02479.
ABSTRACT
Objective: To analyze the mutational landscape of primary and acquired mesenchymal to epithelial transition factor (MET) mutations in non-small cell lung cancer (NSCLC) and investigate the impact of co-mutations on the therapeutic efficacy. Methods: A total of 316 pathologically confirmed NSCLC patients with MET gene mutations treated at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, and Shanghai Chest Hospital, Shanghai Jiao Tong University, between January 2012 and May 2023 were retrospectively enrolled. Demographics, clinicopathological characteristics, and treatment outcomes were collected. Patients were classified into primary MET mutation and acquired MET mutation groups according to the timing of mutation occurrence, and intergroup differences were compared. Treatment responses were evaluated according to the Response Evaluation Criteria in Solid Tumors criteria. Follow-up data on efficacy and progression-free survival (PFS) were collected through telephone calls and medical record review. The follow-up continued until January 2024. Kaplan-Meier survival curves were generated, and log-rank tests were used to compare PFS between patients with different co-mutations receiving tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) therapy. Results: Compared to the acquired mutation group, patients with primary MET mutations were significantly older[median (Q1, Q3) age: 65 (58, 71) vs 59 (51, 64) years; P<0.001], had a higher proportion of males [62.4% (141/226) vs 48.9% (44/90), P=0.028] and a higher proportion of never-smokers [48.7% (110/226) vs 30% (27/90), P=0.002]. In the primary mutation group, TP53 was the most common co-mutation gene (43%, 51/118), followed by EGFR (32%, 38/118) and KRAS (9%, 11/118). In the acquired mutation group, 89% (69/73) of patients retained the EGFR mutation. Aside from EGFR, the most common co-mutation genes were TP53 (63%, 46/73) and CDK4 (12%, 9/73). Among the 62 patients treated with MET-TKI, those with concurrent EGFR-sensitive mutations had a median PFS of 3.1 (95%CI: 2.4-7.2) months, significantly shorter than that of EGFR wild-type patients [18.2 (95%CI: 9.2-22.1) months, P<0.001]. Patients with TP53 co-mutations had a median PFS of 7.5 (95%CI: 6.4-not reached) months, which was significantly longer than TP53 wild-type patients [3.4 (95%CI: 1.8-4.3) months, P=0.035]. Among the 57 patients treated with ICI, those with EGFR-sensitive mutations had a median PFS of 5.3 (95%CI: 2.0-8.2) months, which was significantly shorter than EGFR wild-type patients [10.4 (95%CI: 5.2-not reached) months, P=0.027]. Patients with TP53 co-mutations had a median PFS of 5.9 (95%CI: 3.8-20.4) months, which was longer than TP53 wild-type patients [3.0 (95%CI: 2.0-4.5) months], although the difference was not statistically significant (P=0.344). Conclusions: Primary and acquired MET mutations in NSCLC exhibit distinct genomic characteristics. Patients harboring concurrent EGFR mutations in NSCLC may derive less benefit from MET-TKI and ICI, whereas those harboring TP53 co-mutations tend to experience more favorable outcomes compared with TP53 wild-type NSCLC patients when treated with MET-TKI.
PMID:41320659 | DOI:10.3760/cma.j.cn112137-20250924-02479
