Targeting MET-Mediated Resistance in EGFR-Mutant NSCLC: Advances in Third-Generation TKI Therapy

February 9, 2026 Dr. Michael Lee – Health Editor Health

The management of advanced non-small-cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) has undergone a significant transformation over the past two decades. Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have become the cornerstone of treatment, utilized either as a single agent or in combination with chemotherapy, or the bispecific anti-EGFR MET antibody amivantamab.

Despite the initial efficacy of EGFR TKIs, the development of acquired resistance is nearly global. Identifying the mechanisms driving this resistance is crucial for subsequent treatment strategies. Repeat tissue biopsies performed after disease progression on EGFR TKIs are increasingly crucial, as they can reveal targetable genomic alterations and histological changes responsible for TKI resistance in a subset of patients. These alterations can include,but are not limited to,mutations in MET,HER2,and BRAF,as well as the emergence of small cell lung cancer (SCLC) histology.

The identification of these resistance mechanisms allows for personalized treatment approaches. For example, patients with MET amplification or exon 14 skipping mutations may benefit from therapies targeting MET, such as capmatinib or tepotinib.Similarly, the detection of HER2 alterations can guide the use of HER2-targeted therapies like trastuzumab deruxtecan.

Liquid biopsies, analyzing circulating tumor DNA (ctDNA) in the bloodstream, are also emerging as a valuable tool for detecting resistance mechanisms and monitoring treatment response, offering a less invasive alternative to repeat tissue biopsies. However, ctDNA analysis has limitations, and tissue biopsy remains the gold standard for confirming histological transformations.

Ongoing research is focused on developing novel therapies to overcome EGFR TKI resistance,including next-generation TKIs,combination strategies,and immunotherapies. The continued investigation of resistance mechanisms and the development of innovative treatment approaches are essential for improving outcomes for patients with advanced NSCLC.