Efficacy and safety of chemotherapy or tyrosine kinase inhibitors combined with bevacizumab versus chemotherapy or tyrosine kinase inhibitors alone in the treatment of non-small cell lung cancer: a systematic review and meta-analysis

The meta-analysis evaluated the efficacy and safety of chemotherapy or tyrosine kinase inhibitors combined with bevacizumab versus chemotherapy or tyrosine kinase inhibitors alone in the treatment of non-small cell lung cancer (NSCLC). The PubMed/MEDLINE, Ovid, Web of Science, CNKI, and the Cochrane Library database were searched for eligible randomized controlled trials comparing the combination of chemotherapy or epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with bevacizumab to chemotherapy or EGFR-TKI alone. Main outcome measures were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse effects. The pooled data were analyzed by STATA 12.0 and expressed as hazard ratio (HR) or risk ratio (RR), with their corresponding 95 % confidence intervals (95 % CI). Nine eligible trials comprising 3,547 patients (1,779 for bevacizumab and 1,768 for controls) were included in the study. Chemotherapy or TKIs in combination with bevacizumab significantly prolonged PFS (HR_pfs 0.72, 95 % CI_pfs 0.66–0.79, P _pfs < 0.001) and OS (HR_os 0.90, 95 % CI_os 0.82–0.99, P _os = 0.029) as first-line treatment for NSCLC compared with chemotherapy or TKIs alone. Bevacizumab combination regimens significantly prolonged PFS (HR 0.62, 95 % CI 0.52–0.74, P < 0.001) as second-line treatment; however, no benefit regarding OS was observed with the addition of bevacizumab (HR 0.94, 95 % CI 0.78–1.12, P = 0.479). The bevacizumab group showed increased ORR in both first- and second-line treatments. The high-dose bevacizumab subgroup in combination with chemotherapy showed a statistically significant improvement in OS, PFS, and ORR (HR_os 0.89, 95 % CI_os 0.80–0.99, P _os 0.037; HR_pfs 0.71, 95 % CI_pfs 0.64–0.79, P _pfs < 0.01, RR_orr 1.85, 95 % CI_orr 1.59–2.15, P _orr < 0.001, respectively); however, the low-dose bevacizumab subgroup did not show enhanced OS (HR_os 0.91, 95 % CI_os 0.77–1.07, P _os = 0.263), and a moderate improvement of PFS and ORR (HR_pfs 0.85, 95 % CI_pfs 0.72–1.00, P _pfs = 0.049; RR_orr 1.60, 95 % CI_orr 1.28–2.0, P _orr < 0.001). Erlotinib in combination with bevacizumab significantly prolonged PFS (HR 0.60, P < 0.001, 95 % CI 0.51–0.71) and increased ORR (RR 1.21, 95 % CI 0.98–1.49, P = 0.067) compared with erlotinib alone. A higher incidence of grade ≥3 adverse events such as proteinuria, hypertension, and hemorrhage was observed in the bevacizumab combination group than in the control group without bevacizumab (P _all < 0.05). The addition of bevacizumab to chemotherapy or erlotinib can significantly improve PFS and ORR both in first- and second-line treatments of advanced NSCLC, with an acceptable risk of bleeding events, hypertension, proteinuria, and rash. Combination therapy with bevacizumab and chemotherapy is beneficial regarding OS; however, whether bevacizumab plus erlotinib can prolong OS need further validation.