Clinical and structural insights into concurrent EGFR and MET exon 14 skipping mutations in NSCLC: a multi-center series.

The co-occurrence of epidermal growth-factor receptor (EGFR) mutation and de novo or acquired MET exon 14 skipping (METex14) mutation in non-small-cell lung cancer (NSCLC) is extraordinarily rare. No more than five cases across multiple studies have been well documented. Here, we report the largest EGFR–METex14 co-mutation series to date-seven tumours diagnosed between 2019 and 2024 at three Chinese tertiary hospitals—and compare them with 12 METex14-only and 709 EGFR-only cohorts. Co-mutated tumours were dominated by EGFR-L858R (71%) and frequently harboured high-level MET amplification (57%). Four co-mutations emerged as resistance after first- or third-generation EGFR tyrosine-kinase inhibitors (TKIs), with a median post-acquisition progression-free survival (PFS) of 1.5 months and an overall survival (OS) of less than 6 months. Three de novo tumours exhibited heterogeneous but occasionally durable control. Building on prior evidence that the cytoplasmic kinase domains of EGFR and MET physically interact, we computationally modelled their domain interactions. Compared to EGFR-19del, EGFR-L858R was predicted to have stronger binding affinity to MET, which may contribute to its clinical enrichment. The poor outcomes associated with concurrent EGFR–MET activation likely reflect the enhanced potential of EGFR-L858R to engage MET signaling and may lead to resistance to EGFR-TKIs even without overt MET amplification. In contrast, EGFR-19del showed weaker MET interaction and may retain EGFR-TKI sensitivity unless MET was secondarily upregulated or amplified. These findings highlight the need for routine molecular re-profiling at progression and support prospective trials of dual EGFR/MET blockade administered upfront in de novo co-alteration or at resistance with acquired MET activation.