Neoadjuvant befotertinib plus vorolanib in resectable stage II-IIIB EGFR-mutant NSCLC: a study protocol for the prospective, single-arm phase I/II trial.

BACKGROUND: Neoadjuvant targeted therapy is a promising strategy for resectable non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, but pathological regression remains suboptimal with EGFR-tyrosine kinase inhibitor (TKI) monotherapy. Befotertinib is a third-generation EGFR-TKI, whereas vorolanib is a multi-target antiangiogenic TKI. Combined EGFR and vascular endothelial growth factor receptor (VEGFR) pathway inhibition may enhance tumor regression while preserving surgical feasibility. METHODS: This is a prospective, open-label, single-arm phase I/II study enrolling NSCLC patients with clinically resectable stage II-IIIB harboring sensitizing EGFR exon 19 deletion and/or exon 21 L858R mutations. Phase I uses a 3+3 dose-escalation design to determine the maximum tolerated dose and recommended phase II dose of neoadjuvant befotertinib plus vorolanib. Phase II adopts a two-stage design and evaluates major pathological response after two 21-day neoadjuvant cycles. Patients undergo radiographic assessment after neoadjuvant therapy, followed by radical surgery 4-6 weeks after the last treatment dose. Secondary endpoints include pathological complete response, R0 resection rate, objective response rate, disease control rate, safety, disease-free survival, and overall survival. DISCUSSION: This trial will prospectively explore the feasibility, safety, and preliminary activity of combined third-generation EGFR inhibition and antiangiogenic therapy in resectable stage II-IIIB EGFR-mutant NSCLC. The study may help define whether intensification of neoadjuvant targeted therapy can improve pathological regression in this molecularly selected population. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2500103324).