Background: There is an emerging role of immunotherapy plus chemotherapy (ICC) in the front-line setting for the treatment of Non-Small Cell Lung Cancer (NSCLC) with reported improvement in overall survival (OS) and progression-free survival (PFS). In this review, we highlighted the efficacy and safety of combination regimens as a first-line therapy for NSCLC. Methods: A comprehensive literature search was done on PubMed, Cochrane, Embase, WOS, and Scopus until Dec-2021. The outcomes included progression free survival (PFS) and/or overall survival (OS) and treatment-related adverse events (TRAEs). The inverse variance method was used to generate hazard ratios (HR) with the corresponding 95% confidence intervals for the OS and PFS. Meanwhile, Mantle-Hazard variance was used to create risk ratios for TRAEs. Results: The total eleven randomized controlled trials (RCTs) involving 6,386 patients (pts) were included. 3,850 pts received ICC while 2536 pts received chemotherapy., Four studies each used atezolizumab and pembrolizumab while one study each used nivolumab, tislelizumab, and camrelizumab. The ICC group showed a significant improvement in both PFS (HR, 0.60; 95% CI, 0.54-0.66; p = < 0.00001) and OS (HR, 0.77; 95% CI, 0.68-0.87; p = < 0.0001). Atezolizumab combinations have better PFS and OS compared to the other combinations; HR 0.65 (0.59-0.71) and 0.82 (0.74-0.90), respectively. There was no statistically significant difference between the ICC and control groups regarding TRAEs (RR, 1.07; 95% CI, 0.99-1.16; p = 0.09). Further subgroup analysis is mentioned in the table. Conclusions: The ICC seems to be a promising front-line therapy for NSCLC with superior PFS and OS compared to chemotherapy alone and without significant increase in TRAES.

* p = < 0.00001