Early EGFR inhibition triggers actionable tumour and microenvironmental remodelling in lung cancer.

PURPOSE: Despite widespread use of targeted therapies, little is known about how tumours and their microenvironment respond in the earliest phases of treatment, and whether these early changes reveal new therapeutic opportunities. In this study, we investigated how short-term EGFR inhibition reshapes tumour biology and the tumour microenvironment using comprehensive multi-region and spatial molecular profiling. PATIENTS AND METHODS: Patients with stage IA-IIIA EGFR mutated NSCLC received at least 4 weeks of gefitinib (250 mg daily) before surgery. Multi-region whole-exome and RNA sequencing of resected tumours were compared with a purity-matched treatment-naïve cohort. RESULTS: Thirteen patients received neoadjuvant gefitinib for a median of 1.4 months, achieving objective response and disease control rates of 62% and 100%, respectively. Pathological downstaging occurred in 46% of patients, with major pathological response in 8%. Deep genomic and transcriptomic profiling revealed rapid tumour and microenvironmental adaptation to EGFR inhibition without emergence of common acquired resistance mutations such as EGFR T790M. Compared with treatment-naïve tumours, on-treatment tumours showed reduced tumour purity, decreased EGFR amplification, increased immune regulatory and inflammatory gene expression, and a metabolic shift from glycolysis to oxidative phosphorylation, spatially validated. CONCLUSIONS: These findings show that early EGFR inhibition triggers coordinated remodelling of tumour cells and the microenvironment, uncovering new therapeutic vulnerabilities and opening a window for rational combination strategies to improve outcomes in EGFR mutated NSCLC.