OBJECTIVES: The objective was to evaluate the clinical efficacy and safety of combined targeted therapy against EGFR and VEGF pathways in patients with previously treated advanced Non–small-cell lung cancer (NSCLC). METHODS: Studies were retrieved from Embase, Pubmed and Cochrane databases using relevant search strategies. Randomized controlled trials which compared combined targeted therapy with control groups (including single EGFR or VEGF inhibition or/and chemotherapy) were selected as per pre-defined inclusion criteria. Outcomes assessed included overall survival (OS), progression free survival (PFS), objective response rate (ORR), and adverse events (AEs). Two reviewers independently extracted data from the included studies. Data was analysed using RevMan (v5.3). RESULTS: Of the 876 studies identified, seven studies with 3347 patients were included for meta-analysis. In total, 1688 patients were randomised to combination therapy and 1659 were randomised to control groups. Median OS (range 8- 13.7 vs. 4.5- 13.4 months), PFS (range 3.4- 4.7 vs. 1.9- 4.8 months) and ORR (range 4.6% -26.2% vs. 3.1% - 12.5%) was better with combination therapy vs. control group therapies. In two studies, patients on vandetinib and docetaxel combination therapy showed a significant improvement (p<0·0001) in PFS and overall response rate versus those randomly assigned to receive docetaxel only. Results of meta- analysis demonstrate that combined targeted therapy has better OS (WMD: 1.23 [95% CI: 0.06, 2.41], p = 0.04), PFS (WMD: 1.07 [95% CI: 0.7, 1.45], p < 0.00001) and ORR (OR: 1.85 [95% CI: 1.49, 2.31], p < 0.00001). The AE profile (gastrointestinal, vascular, infectious and blood disorders) was better in the control group therapies. CONCLUSIONS: Survival benefit and response rate with combined inhibition therapy against EGFR and VEGF was better than the VEGF or EGFR alone inhibition. Combination therapy was associated with increased toxicity resulting in low compliance and dose reduction or discontinuation.