Background: This meta-analysis aimed to explore if immunotherapy or chemotherapy alone or in combination is a better first line treatment strategy for advanced non-small cell lung cancer (NSCLC) patients. Methods: Electronic databases including Google Scholar, PMC, PubMed, EMBASE, Scopus and the major conference proceedings were searched for relevant randomized controlled trials (RCTs) comparing outcomes of immune-checkpoint inhibitor combined with chemotherapy or immune-checkpoint inhibitor alone over chemotherapy alone in patients with advanced NSCLC without previous treatment. Study heterogeneity was assessed using the I2 test. Results: A total of 14 RCTs including 8,081 treatment naïve advanced NSCLC patients were enrolled in this study. Our results showed that in comparison to chemotherapy alone, introducing immunotherapy into first-line chemotherapy has significant benefit in tumor response (RR, 1.27; 95% CI, 1.09 to 1.48), progression-free survival (PFS) (HR, -0.43; 95% CI, -0.56 to -0.31), and overall survival (OS) (HR, -0.30; 95% CI, -0.45 to -0.14) but with an increased risk of grade3 - 5 toxicity (RR, 1.11; 95% CI, 1.04 to 1.18). The pooled results of comparison of immune therapy alone with chemotherapy alone in selected patients with positive expression of Programmed Death-ligament (PD-L1) or with a high tumor mutational burden, demonstrated similar tumor response (RR, 1.13; 95% CI, 0.88 to 1.46), 3 - 5 grade toxicity (RR, 0.69; 95% CI, 0.40 to 1.19) and long-term outcomes, including OS (HR, -0.20; 95% CI, -0.43 to 0.03) and PFS (HR, -0.24; 95% CI, -0.61 to 0.14). Conclusions: Our meta-analysis showed the superiority of combination therapy over monotherapy with chemotherapeutic agents in terms of tumor response, and long-term survival, but with an increased the 3 - 5 grade toxicity. And immune-checkpoint inhibitors alone showed similar tumor response, toxicity and long-term outcomes compared to platinum-based chemotherapy in selected patients.
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