Abstract
Brain metastases are common in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) and remain clinically challenging despite the improved central nervous system activity of third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs). Because direct comparisons between active first-line combination strategies are limited, this systematic review and network meta-analysis (NMA) evaluated the relative efficacy and safety of EGFR-TKI-based combinations in this population. PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to December 31, 2025. Randomized controlled trials (RCTs) and non-randomized comparative studies were eligible if they enrolled patients with EGFR-mutated NSCLC and brain metastases and compared EGFR-TKI monotherapy with EGFR-TKI-based combinations incorporating chemotherapy, anti-angiogenic therapy, radiotherapy, or bispecific antibody therapy. Bayesian NMAs were performed for overall survival (OS), progression-free survival (PFS), and intracranial PFS (iPFS). RCT-only analyses were conducted as robustness assessments. Grade ≥ 3 treatment-related adverse events (TRAEs) were summarized descriptively. Forty-eight studies involving 5,432 patients were included, of which 17 were RCTs. In the overall network, EGFR-TKI plus anti-angiogenic therapy showed the most favorable OS estimate versus monotherapy (HR, 0.63; 95% CI, 0.49-0.80), whereas EGFR-TKI plus chemotherapy showed the most favorable estimates for PFS (HR, 0.52; 95% CI, 0.44-0.61) and iPFS (HR, 0.36; 95% CI, 0.25-0.52). RCT-only analyses most consistently supported the PFS benefit of EGFR-TKI plus chemotherapy; OS rankings were less definitive, and randomized iPFS evidence remained sparse. Radiotherapy-related results were exploratory because the radiotherapy node pooled WBRT, SRS/SRT, mixed approaches, and variable dose-fractionation schedules. EGFR-TKI plus chemotherapy showed the most consistent evidence for delaying progression. The apparent OS advantage of EGFR-TKI plus anti-angiogenic therapy, and findings for radiotherapy- and bispecific antibody-based combinations, should be interpreted cautiously. Treatment selection should be individualized according to treatment goals, EGFR-TKI generation, intracranial disease burden, expected toxicity, and patient tolerability.