Concurrent icotinib and definitive radiotherapy followed by detection of an EGFR exon 20 insertion at disease progression in unresectable stage III EGFR S768I-mutant lung adenocarcinoma: a case report.

Uncommon EGFR mutations account for approximately 10-15% of all EGFR-mutated non-small cell lung cancer (NSCLC), and the optimal management of unresectable stage III disease harboring isolated EGFR S768I mutations remains poorly defined. We report the case of a 55-year-old woman with unresectable stage IIIC lung adenocarcinoma harboring an isolated EGFR S768I mutation. Because platinum-based chemotherapy was discontinued owing to severe gastrointestinal toxicity, she received concurrent icotinib and definitive intensity-modulated radiotherapy (IMRT), achieving a partial response with a progression-free survival of approximately 8 months and only grade 1 oral mucositis. At disease progression, repeat biopsy followed by next-generation sequencing (NGS) identified an EGFR exon 20 insertion (p.V769_D770insSVV) together with a marked reduction in the abundance of the original EGFR S768I mutation. As comprehensive baseline genomic profiling was unavailable, these findings should be interpreted cautiously and may represent either treatment-associated molecular alteration or expansion of a pre-existing low-frequency resistant subclone rather than definitive acquisition of a new mutation. Subsequent treatment with afatinib, ivonescimab plus chemotherapy, and sunvozertinib was selected according to dynamic molecular profiling. This case suggests that concurrent icotinib and definitive radiotherapy may represent a feasible individualized treatment option for carefully selected patients with unresectable stage III EGFR-mutant NSCLC who are unable to tolerate standard concurrent chemoradiotherapy. More importantly, it highlights the value of repeat biopsy and comprehensive genomic profiling for interpreting molecular changes at disease progression and guiding subsequent individualized treatment in patients with uncommon EGFR mutations. However, these observations are derived from a single case and require validation in larger prospective studies.