For the roughly 1–3% of non-small cell lung cancer patients harboring MET exon 14 skipping mutations, treatment sequencing decisions carry outsized consequences — yet real-world data comparing available MET inhibitors remain sparse. This small but carefully characterized cohort sheds light on a clinically underserved molecular subtype and hints at meaningful differences between two generations of MET-targeted therapy.
In 24 METex14-mutated NSCLC patients who underwent genetic sequencing prior to treatment, median progression-free survival across the full cohort reached 7.0 months. The split between therapeutic approaches was notable: twelve patients receiving crizotinib, a first-generation type Ia MET inhibitor, achieved a median PFS of 6.1 months with a disease control rate of 66.7%, and half progressed within just three months. By contrast, twelve patients treated with vebreltinib, a more selective type Ib inhibitor, reached a median PFS of 8.7 months with a disease control rate of 91.7%, and half surpassed the 7-month mark. The difference did not achieve statistical significance, almost certainly reflecting the small sample size. Resistance mechanisms were diverse: an acquired D1228N MET kinase domain mutation, EGFR amplification, and one case of histologic transformation to pulmonary sarcomatoid carcinoma. Importantly, two patients responded to sequential type Ib therapy after type Ia failure, suggesting non-overlapping resistance profiles. Complementary RNA sequencing of 11 METex14 cases from TCGA characterized the tumor immune microenvironment, and one patient with high PD-L1 expression achieved 13 months PFS on camrelizumab plus endostar.
This study is best understood as hypothesis-generating rather than practice-changing. With only 12 patients per arm, even large absolute PFS differences lack the statistical power to drive treatment guidelines. Yet the direction of the signal aligns with emerging data from dedicated METex14 trials showing that more selective type Ib inhibitors — which avoid the off-target kinase activity of crizotinib — may reduce toxicity and delay resistance. The finding that sequential MET TKI therapy can rescue some patients after first-line failure is clinically relevant and warrants prospective evaluation. The patient-derived organoid component, though limited to three cases, points toward future precision oncology workflows for this rare NSCLC subtype.