Background:
Tyrosine kinase inhibitors (TKIs) are standard treatment options for
non-small cell lung cancer (NSCLC) with
epidermal growth factor receptor (EGFR) mutations. Increasing clinical investigations have explored the value of EGFR-TKIs plus antiangiogenic drugs as the first-line treatment for EGFR-mutated NSCLC. Methods: We systematically searched PubMed, Cochrane Library, and EMBASE for randomized controlled trials (RCTs) investigating EGFR-TKIs administered with or without
antiangiogenic agents for advanced EGFR-mutated NSCLC. The latest RCT that was presented orally at the 2019 European Society for Medical Oncology Congress was obtained online. The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rates (DCRs), and grade 3 or higher adverse events (AEs). Results: We included seven articles on five trials with 1,226 patients. The interventions for the experimental group were the first-generation EGFR-TKI
erlotinib combined with
bevacizumab (four studies) or
ramucirumab (one study), and
erlotinib monotherapy (four studies) or
erlotinib plus placebo (one study) for the control group. All studies reached their primary study endpoints (i.e., PFS). Compared to
erlotinib monotherapy,
erlotinib plus
antiangiogenic agents remarkably prolonged PFS [hazard ratio (HR) = 0.59, 95% confidence interval (CI) = 0.51-0.69, P = 0.000]; however, ORR, DCR, and OS were similar between the two groups. The overall grade 3-5 AEs increased in combination group (OR = 5.772, 95% CI = 2.38-13.94, P = 0.000), particularly the incidence of
diarrhea (OR = 2.51, 95% CI = 1.21-5.23, P = 0.014), acneiform (OR = 1.815, 95% CI = 1.084-3.037, P = 0.023),
hypertension (OR = 6.77, 95% CI = 3.62-12.66, P = 0.000), and
proteinuria (OR = 13.48, 95% CI = 4.11-44.22, P = 0.000). Additionally, subgroup analysis demonstrated that Asian patients could significantly benefit from combination
therapy (HR = 0.59, 95% CI = 0.50-0.69, P = 0.000). Patients with exon 19 deletions (HR = 0.61, 95% CI = 0.49-0.75, P = 0.000) and 21 Leu858Arg mutations (HR = 0.59, 95% CI = 0.47-0.73, P = 0.000) had almost equivalent PFS benefits when treated with double-blocking
therapy. Patients with
brain metastases at baseline in the combination group had a trend toward better PFS (HR = 0.55, 95% CI = 0.30-1.01, P = 0.001). Conclusions:
Erlotinib plus
bevacizumab or
ramucirumab in EFGR-mutated NSCLC first-line setting yielded remarkable PFS benefits; however, this was accompanied by higher AEs.
Epidermal growth factor receptor-TKI plus
antiangiogenic agent therapy may be considered a new option for advanced EGFR-mutated NSCLC patients.