Crizotinib or vebreltinib response and resistance in advanced non-small cell lung cancer with MET exon 14 skipping

BACKGROUND: MET exon 14 skipping (METex14) mutations account for 1-3% of non-small cell lung cancer (NSCLC) cases. Although MET tyrosine kinase inhibitors (TKIs) and immunotherapy have improved survival, resistance remains a challenge. METHODS: This real-world analysis includes 24 METex14-mutated NSCLC patients who underwent genetic sequencing before MET TKI treatment. RNA sequencing data from 11 METex14 mutated NSCLC patients in the TCGA database were analyzed to characterize tumor immune microenvironment composition and functional profiles. Patient-derived organoids (PDOs) were established from malignant effusion or tissue of three patients to suggest treatment responses. RESULTS: In this cohort of 24 METex14-mutated NSCLC patients, the overall median progression-free survival (mPFS) was 7.0 months. While crizotinib (n = 12) showed mPFS of 6.1 months (disease control rate DCR 66.7%) with 50% progressing within 3 months, vebreltinib (n = 12) demonstrated longer mPFS of 8.7 months (DCR 91.7%), with half exceeding 7.0 months. However, these differences did not reach statistical significance. Notably, two patients benefited from sequential type Ib MET TKI therapy after type Ia failure. Resistance mechanisms included acquired D1228N MET mutation, EGFR amplification, and histologic transformation to pulmonary sarcomatoid carcinoma (n = 1). One patient with high PD-L1 expression (TPS ≥ 50%) achieved 13.0 months PFS with camrelizumab/endostar immunotherapy. RNA sequencing revealed PD-L1-high tumors harbored an immune-favorable microenvironment. Patient-derived organoid (PDO) drug test demonstrated preliminary qualitative consistency with clinical outcomes, supporting their predictive value. CONCLUSIONS: While vebreltinib appears clinically advantageous over crizotinib for METex14-mutated NSCLC, the therapeutic benefits did not reach statistical significance in this study. The observed differential response patterns and resistance mechanisms suggest distinct biological behaviors to type Ia and Ib MET TKIs that warrant further investigation. These findings underscore the need for larger prospective studies to validate the potential superiority of vebreltinib and to better characterize the molecular determinants in NSCLC.