Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥ grade 3). Heterogeneity was assessed with Cochrane Q-statistic. Random effects were used due to significant heterogeneity among studies. Results: Seven phase 2 & 3 RCTs (Keynote-021,189, 407, IMpower-131, 150, checkmate-227, and Govindan et al) including 3785 patients with advanced NSCLC were included in the analysis. IMpower 150 trial allowed EGFR or ALK mutated patients. The study arm used standard treatment regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab, while control arm used only standard treatment regimens. The pooled HR for PFS was 0.65 (95% CI: 0.56-0.77; P=0.00001), the pooled HR for OS was 0.73 (95% CI: 0.59-0.90; P=0.003), and the pooled RR for ORR was 1.45 (95 CI: 1.17-1.8; P=0.0007). The pooled RRs for all-grade AEs and high-grade AEs were 1.1 (95% CI: 1-1.21; P=0.05) and 1.28 (95% CI: 1.13-1.46; P=0.0001), respectively. Conclusions: Adding immunotherapy to standard regimen significantly improves PFS, OS, and ORR for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.