First-line integration of Local Ablative Therapy (LAT) with EGFR Tyrosine Kinase Inhibitors (TKIs) in advanced EGFR+ NSCLC: A Systematic Review and Meta-Analysis

Background: Systemic intensification strategies improve outcomes in advanced EGFR-mutated non-small cell lung cancer (NSCLC) but increase toxicity. Integrating local ablative therapy (LAT) with first-line EGFR tyrosine kinase inhibitor (TKI) monotherapy represents an alternative approach to enhance disease control while preserving long-term tolerability. Methods: MEDLINE, Embase and Elicit were searched through December 2025. The protocol was registered in PROSPERO (CRD420251244650). Randomised and non-randomised comparative studies evaluating EGFR TKI with or without LAT integrated into first-line treatment, either upfront or as consolidative therapy, were included in quantitative meta-analyses. Single-arm and non-comparative studies were analysed descriptively. HRs were pooled using random-effects models. Prespecified subgroup analyses explored: disease burden, LAT timing, study design (prospective vs retrospective), LAT site, and TKI generation. Results: Thirty-one studies met inclusion criteria, including 24 comparative studies (6 randomised, 2 prospective non-randomised and 16 retrospective). LAT integration significantly improved progression-free survival (HR 0.45, 95%CI 0.37-0.55) and overall survival (HR 0.52, 95%CI 0.40-0.67) versus EGFR TKI alone. Benefits were consistent across oligometastatic and unselected populations, upfront and consolidative strategies, LAT sites (primary tumor +/- metastatic sites), TKI generations, and prospective/retrospective studies. Radiotherapy-related toxicities, particularly pneumonitis, were more frequent with LAT, but grade ≥3 events were uncommon and no unexpected safety signals emerged. Conclusions: Across a heterogeneous evidence base, integrating LAT into first-line EGFR TKI therapy is associated with improved PFS and OS with acceptable toxicity. These findings support further prospective investigation to better define patients election, optimal timing, and integration with contemporary systemic combination strategies.