Antibody-drug conjugates outperform chemotherapy in EGFR-TKI-resistant NSCLC: a Bayesian network meta-analysis

Background: While developments in targeted therapy have marked a new epoch for non-small cell lung cancer (NSCLC) patients harboring actionable genomic alterations, the management of individuals resistant to epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a formidable challenge. Objectives: This study was designed to evaluate the comparative efficacy and safety of available therapeutic regimens and to identify the optimal treatment strategy for patients with disease progression following EGFR-TKI therapy. Design: This is a systematic review and Bayesian network meta-analysis. Data sources and methods: Databases including PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov, along with conference proceedings from January 1, 2020, to June 1, 2025, were searched. Randomized controlled trials (RCTs) assessing treatment options for advanced NSCLC patients resistant to EGFR-TKIs were eligible. We identified the optimal therapeutics through comparison of the surface under the cumulative ranking curves (SUCRA). Results: Overall, 19 RCTs involving 4,039 participants were identified. Meta-analysis indicated that sacituzumab tirumotecan (Sac-TMT) significantly improved progression-free survival (PFS; hazard ratio [HR] 0.20, 95% credible interval [CI] 0.13–0.30) and overall survival (OS; HR 0.36, 95% CI 0.20–0.66) compared to conventional chemotherapy as evidenced by its superior SUCRA values (0.997 for PFS and 0.946 for OS). Datopotamab deruxtecan (Dato-DXd) also demonstrated clinically meaningful efficacy outcomes. Specifically, Sac-TMT showed statistically superior PFS benefits relative to nearly all comparator regimens, including immune checkpoint inhibitor (ICI)-based and bispecific antibody (bsAb)-based strategies (all p < 0.05). Amivantamab in combination with lazertinib and chemotherapy (SUCRA = 0.816) and ivonescimab combined with chemotherapy (SUCRA = 0.779) both exhibited capabilities in prolonging PFS. Notably, the triplet regimen was associated with the highest incidence of severe-grade AEs compared to all other treatment options. Conclusion: Sac-TMT, Dato-DXd, and bsAbs-based regimens were identified as the most efficacious options with manageable toxicity for advanced NSCLC patients who progressed after EGFR-TKIs. These findings underscore the pivotal role of innovative therapeutic agents, illuminating potential treatment avenues for this difficult-to-treat refractory population. Trial registration: This study was registered as INPLASY202510014.