Optimal treatment strategies for unresectable stage III

Background: The PACIFIC regimen (consolidation durvalumab following chemoradiotherapy) is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). With the publication of data from the phase III LAURA trial and the emergence of real-world evidence regarding sequential toxicity, concurrent chemoradiotherapy followed by sequential targeted therapy with EGFR tyrosine kinase inhibitors (TKIs) is recommended for patients with EGFR mutations. However, the optimal combination regimen remains to be determined. Methods: We systematically searched the PubMed, Embase, Cochrane Library, and Web of Science databases to identify randomized controlled trials (RCTs) and high-quality retrospective studies comparing various therapeutic strategies for unresectable stage III EGFR-mutated NSCLC. The primary endpoints were progression-free survival (PFS) and overall survival (OS), while secondary endpoints included the objective response rate (ORR) and safety profiles. A network meta-analysis (NMA) was performed using a Bayesian random-effects model. Hazard ratios (HRs), odds ratios (ORs), and their corresponding 95% credible intervals (CrIs) were calculated. Results: A total of 12 studies involving 1,529 patients were analyzed to compare six therapeutic strategies: consolidation durvalumab following chemoradiotherapy (CRT+Durva), CRT alone, consolidation EGFR-TKIs after CRT (CRT+EGFR-TKI), EGFR-TKI monotherapy, EGFR-TKI in combination with chemotherapy (EGFR-TKI+Chemo), and EGFR-TKI integrated with radiotherapy (EGFR-TKI+RT) via induction, concurrent, or consolidation sequencing. NMA revealed that CRT+EGFR-TKI was the only strategy to demonstrate a statistically significant improvement in OS compared to CRT alone (HR = 0.63, 95% CrI: 0.41-0.94), while also achieving the highest ORR. EGFR-TKI+RT (chemotherapy-free regimen) ranked first for PFS (HR = 0.14, 95% CrI: 0.06-0.33) and exhibited a favorable safety profile, associated with the lowest risk of severe radiation pneumonitis (RP). Notably, CRT+Durva failed to yield a survival benefit (PFS: HR = 0.75; OS: HR = 0.82) and was characterized by higher toxicity. An RCT-only sensitivity analysis demonstrated consistent PFS benefits and a comparable OS trend (HR = 0.68, 95% CrI: 0.33-1.4), validating the integration of real-world data to maintain adequate statistical power. Conclusions: For unresectable stage III EGFR-mutated NSCLC, CRT+EGFR-TKI represents the optimal strategy for extending OS. Conversely, the EGFR-TKI+RT (chemotherapy-free regimen) approach provides a superior balance between prolonged PFS and clinical tolerability. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420261285935.