Efficacy and Safety of EGFR-TKI Combined with Chemotherapy for the First-line Treatment of EGFR-mutated Advanced Non-small Cell Lung Cancer: a Meta-analysis

Background Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has become a standardized treatment option for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC), but clinical findings of unavoidable primary or secondary resistance ultimately lead to disease progression. For this reason, finding markers for early prediction of effective populations and exploring optimized therapeutic regimens to prolong or reverse secondary resistance have become the focus of research at home and abroad. Objective To systematically evaluate the efficacy and safety of EGFR-TKI combined with chemotherapy for the first-line treatment of EGFR-mutated advanced non-small cell lung cancer based on data from domestic and international literature. Methods Three professionally recognized databases, PubMed, Embase, and Cochrane Library, were searched for randomized controlled trials eligible for the efficacy and safety of EGFR-TKI combination chemotherapy versus single-agent EGFR-TKI for the first-line treatment of patients with EGFR-mutated advanced non-small-cell lung cancer published from the time of construction to November 2023.Data on progression-free survival (PFS), overall survival (OS), objective remission rate (ORR), disease control rate (DCR), and grade≥3 adverse events were collected and analyzed by two investigators who independently screened the literature, extracted the data, and evaluated the risk of bias of the included studies. Subgroup analyses were performed based on baseline clinical characteristics, and data were statistically analyzed using RevMan 5.4.1. Results Ten eligible studies with a total of 2 029 patients were included, including 1 049 patients in the experimental group of EGFR-TKI combined with standard chemotherapy; and 980 patients in the control group of EGFR-TKI alone. Meta-analysis showed that compared with EGFR-TKI monotherapy, EGFR-TKI combination chemotherapy prolonged PFS (HR=0.54, 95%CI=0.49-0.60, P<0.000 01) and OS (HR=0.69, 95%CI=0.59-0.79, P<0.000 01). Compared with EGFR-TKI monotherapy, EGFR-TKI combination chemotherapy improved ORR (OR=1.95, 95%CI=1.57-2.42, P<0.000 01) and DCR (OR=1.76, 95%CI=1.13-2.74, P=0.01) in patients with advanced NSCLC with EGFR mutations. In patients with concomitant brain metastases, EGFR-TKI combination chemotherapy prolonged PFS (HR=0.42, 95%CI=0.34-0.52, P<0.000 01) and OS (HR=0.69, 95%CI=0.51-0.94, P=0.02) in patients with EGFR-mutated advanced NSCLC compared with single-agent EGFR-TKI treatment.In patients without brain metastases at baseline, EGFR-TKI combination chemotherapy prolonged PFS compared with single-agent EGFR-TKI treatment in patients with advanced NSCLC with EGFR mutations (HR=0.62, 95%CI=0.53-0.72, P<0.000 01). The incidence of grade ≥3 adverse reactions was higher with EGFR-TKI combination chemotherapy than with single-agent EGFR-TKI treatment in patients with advanced NSCLC with EGFR mutations (OR=4.25, 95%CI=2.74-6.61, P<0.000 01). The incidence of grade ≥3 adverse reactions was higher in the combination therapy group than in the monotherapy group. Conclusion EGFR-TKI combination chemotherapy significantly prolongs first-line PFS and OS in EGFR-mutated advanced non-small cell lung cancer, especially in patients with baseline brain metastases. The incidence of adverse events was increased in the combination therapy group, particularly the incidence of grade ≥3 hematologic toxicity, but was overall safe and manageable.