Comparative efficacy and safety of first-line combination therapies with third-generation EGFR-TKIs in advanced <i>EGFR</i> -mutant NSCLC: A systematic review and network meta-analysis.

Abstract

e20745 Background: While third-generation EGFR tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for advanced EGFR-mutant non-small cell lung cancer (NSCLC), various combination strategies have been developed to overcome resistance and deepen responses. Direct comparisons between these strategies are lacking, leaving their relative efficacy and safety profiles undefined. Methods: We conducted a Bayesian network meta-analysis. Randomized controlled trials (RCTs) comparing five first-line strategies, third-generation EGFR-TKI monotherapy, or its combination with chemotherapy, anti-angiogenic agents, bispecific antibodies, or local consolidative therapy, were systematically searched in PubMed, Embase, and the Cochrane Library up to November 1, 2025. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), grade ≥3 adverse events (AEs), and overall survival (OS). Treatments were ranked using the surface under the cumulative ranking curve (SUCRA). Results: Nine RCTs (N = 2,750) were included. All combination strategies demonstrated superior progression-free survival (PFS) compared to TKI monotherapy. EGFR-TKI plus chemotherapy provided the most pronounced and consistent PFS benefit (HR 0.54, 95% CI 0.44–0.66) and achieved the highest surface under the cumulative ranking curve (SUCRA) value (0.8544) . A pairwise meta-analysis of available overall survival (OS) data also favored combination strategies (pooled HR 0.76, 95% CI 0.65-0.88) . In the OS subgroup analysis, patients aged under 65 years, harboring the 19del mutation, and with CNS metastases demonstrated significant differences. However, all combinations were associated with an increased risk of grade 3 or higher adverse events (AEs). Conclusions: For the first-line treatment of advanced EGFR-mutant NSCLC, combination strategies based on a third-generation EGFR-TKI improve PFS and show OS benefit compared to monotherapy. EGFR-TKI plus chemotherapy represents the current evidence-based benchmark for maximizing disease control. EGFR-TKI plus bispecific antibody emerges as a potent chemotherapy-sparing alternative with validated OS benefit. Treatment decisions require individualized calibration of the disease's aggressiveness against the patient's tolerance for increased toxicity.