Treatment-Emergent Isolated EGFR C797S Mutation Following First-Line Osimertinib-Based Combination Therapy: A Case...

Osimertinib is the standard first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC), although acquired resistance remains inevitable. The EGFR C797S mutation is a recognized on-target resistance mechanism; however, the T790M-negative/C797S-only subtype following frontline osimertinib-based combination therapy is rarely reported. We describe a 44-year-old Vietnamese never-smoking woman diagnosed with stage IV lung adenocarcinoma harbouring EGFR exon 21 L858R mutation. First-line treatment with pemetrexed-carboplatin plus osimertinib achieved a near-complete response, followed by maintenance osimertinib monotherapy. After 26 months of disease control, radiologic progression occurred with recurrent bilateral pulmonary metastases and right supraclavicular lymphadenopathy. Repeat biopsy and next-generation sequencing identified persistent EGFR L858R (VAF 13.92%) and acquired EGFR C797S (VAF 6.19%) without detectable T790M, consistent with a C797S-only resistance profile. Subsequent gefitinib plus bevacizumab therapy produced a rapid radiologic response with near-complete resolution of contralateral pulmonary lesions, suggesting retained sensitivity to reversible EGFR tyrosine kinase inhibitor-based therapy in C797S-only disease.