Early EGFR Inhibition Triggers Actionable Tumor and Microenvironmental Remodeling in Lung Cancer

Despite widespread use of targeted therapies, little is known about how tumors 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 epidermal growth factor receptor (EGFR) inhibition reshapes tumor biology and the tumor microenvironment using comprehensive multiregion and spatial molecular profiling.

Patients with stage IA-IIIA EGFR-mutated non-small cell lung cancer (NSCLC) received at least 4 weeks of gefitinib (250 mg daily) before surgery. Multiregion whole-exome and RNA sequencing of resected tumors were compared with a purity-matched treatment-naïve cohort.

Thirteen patients received neoadjuvant gefitinib for a median of 1.4 months, achieving objective response and disease control rates of 62% and 100%, respectively. Pathologic downstaging occurred in 46% of patients, with major pathologic response in 8%. Deep genomic and transcriptomic profiling revealed rapid tumor and microenvironmental adaptation to EGFR inhibition without emergence of common acquired resistance mutations such as EGFR T790M. Compared with treatment-naïve tumors, on-treatment tumors showed reduced tumor purity, decreased EGFR amplification, increased immunoregulatory and inflammatory gene expression, and a metabolic shift from glycolysis to oxidative phosphorylation, spatially validated.

These findings show that early EGFR inhibition triggers coordinated remodeling of tumor cells and the microenvironment, uncovering new therapeutic vulnerabilities and opening a window for rational combination strategies to improve outcomes in EGFR-mutated NSCLC.

This study demonstrated that neoadjuvant gefitinib is safe, feasible, and effective. Multiregion and spatial genomic and transcriptomic sequencing provided unique insight into adaptive response in the tumor and microenvironment. This window-of-opportunity study uncovered the potential for rational combination approaches to improve therapeutic efficacy in EGFR-mutated NSCLC.