First-line EGFR-TKI plus chemotherapy improves survival in advanced EGFR-mutated NSCLC: an updated systematic review and meta-analysis of contemporary trials

While EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are widely used as first-line treatment in advanced EGFR-mutated non-small cell lung cancer (NSCLC), acquired resistance leads to inevitable disease progression. Recent trials have evaluated adding chemotherapy to EGFR-TKIs, with inconsistent results and unclear clinical implications. We performed an updated meta-analysis to assess the efficacy and safety of this combination and inform treatment selection. A systematic review and meta-analysis (PROSPERO, CRD420251206930) of clinical trials were conducted. Eligible studies enrolled patients with advanced EGFR-mutated NSCLC and compared first-line EGFR-TKI therapy with or without chemotherapy. We searched EMBASE, PubMed, Web of Science, MEDLINE, and Scopus from inception to Nov 7, 2025. The primary outcomes were progression-free survival (PFS) and overall survival (OS), expressed as pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Fixed- or random-effect models were applied according to between-study heterogeneity, with random-effect sensitivity analyses performed for the primary outcomes. Ten eligible studies involving 2162 patients (combination therapy: 1108 patients; monotherapy: 1054 patients) were included. The pooled effects showed that combination therapy achieved a better PFS (HR = 0.58; 95%CI: [0.52, 0.65]; P < 0.01) and OS (HR = 0.73; 95%CI: [0.65, 0.82]; P < 0.01) than monotherapy. Patients receiving combination therapy also achieved a higher objective response rate (ORR) (OR = 1.77; 95%CI: [1.44, 2.17]; P < 0.01). These efficacy gains were accompanied by an increased risk of grade ≥ 3 adverse events (OR = 3.73; 95%CI: [2.52, 5.53]; P < 0.01), although no significant difference in treatment-related mortality was observed (OR = 2.33; 95%CI: [0.77, 7.03]; P = 0.13). First-line EGFR-TKI plus chemotherapy was associated with improved survival and tumor response but increased toxicity compared with EGFR-TKI monotherapy. Given the predominance of first-generation EGFR-TKI data, these findings support individualized benefit–risk assessment rather than a universal preference for combination therapy.