ETV6-NTRK3 as a resistance mechanism to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors: favorable response after combination of osimertinib and entrectinib: a case report and literature review

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), typified by osimertinib, yield substantial efficacy in non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. However, acquired tumor resistance to these agents is unavoidable and driven by heterogeneous mechanisms, which dictate subsequent therapeutic selection. A key resistance pathway involves activation of alternative oncogenic signaling; beyond classic alterations (C797S mutation, MET amplification, HER2 variants), rare oncogenic drivers may also emerge. We report a case of an EGFR exon 19 deletion-positive NSCLC patient who developed osimertinib resistance after first-line therapy. Second-line rebiopsy identified an ETV6-NTRK3 (neurotrophic tyrosine receptor kinase [NTRK]) fusion. Combination therapy with osimertinib and entrectinib induced regression of pulmonary lesions, but the patient ultimately discontinued all targeted agents due to the development of severe hepatorenal failure and Escherichia coli-associated sepsis. This case highlights the need for additional research into the safety profile of EGFR-TKI/NTRK inhibitor combination regimens in resistant NSCLC.