Abstract
BACKGROUND: Patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR L858R mutations have a poorer prognosis than those with exon 19 deletions and exhibit variable responses to first-generation EGFR tyrosine kinase inhibitors (TKIs). Evidence on the use of gefitinib plus bevacizumab in this subgroup remains limited. This study aimed to evaluate the efficacy and safety of gefitinib combined with bevacizumab and to investigate plasma circulating tumor DNA (ctDNA) biomarkers in this patient population. METHODS: In this randomized trial, 81 stage III/IV L858R-mutant NSCLC patients received gefitinib alone or gefitinib plus bevacizumab. The primary endpoint was progression-free survival (PFS), with secondary endpoints including objective response rate (ORR) and safety. Plasma ctDNA was evaluated for prognostic value and detection of treatment-related resistance. RESULTS: Combination therapy significantly improved median PFS (15.1 vs. 8.2 months, P<0.01) and ORR (90.2% vs. 59.0%, P<0.01) compared to gefitinib alone. Adverse effects were similar, with hypertension occurring exclusively in the combination group. Positive ctDNA at 6 weeks post-treatment correlated with shorter PFS in both groups. A decline in maximal somatic variant allelic frequency (maxVAF) exceeding 98% was associated with improved PFS in the combination group (17.0 vs. 5.4 months, P<0.01). The combination group showed a trend towards lower EGFR T790M mutation frequency (30.8% vs. 58.8%, P=0.16). CONCLUSIONS: Gefitinib plus bevacizumab shows promising efficacy and tolerability in EGFR-mutated NSCLC patients. Plasma ctDNA assessment facilitates the evaluation of treatment efficacy, monitoring disease progression, and informing second-line treatment options. TRIAL REGISTRATION: ClinicalTrials.gov NCT04425187.