Background: PD-1/PD-L1 inhibitors prolong survival in treatment-naïve, locally advanced, and metastatic non-small cell lung cancer (NSCLC) with positive PD-L1 expression (> 1%/ > 50%). Recent evidence has suggested that tumors with < 1% PD-L1 expression may also be predictive of PD-1/PD-L1 inhibiting agents.Methods: Systematic review and meta-analysis were conducted of randomized controlled trials (RCTs) evaluating PD-1/PD-L1 inhibitors that have assessed tumors with < 1% PD-L1 expression (negative PD-L1 expression). PD-1/PD-L1 inhibitors–chemotherapy combinations (PC) were compared with histology-selected chemotherapy with respect to overall survival (OS) and progression-free survival (PFS).Results: Twelve RCTs comprising 5410 participants (PD-1/PD-L1 inhibitors–chemotherapy: 3051; chemotherapy: 2359) met the inclusion criteria. Tumors with PD-L1 expression < 1% were evident in 38.9% of the pooled study population. A significant OS [hazard ratio (HR) 0.71 95% confidence interval (CI) 0.63–0.80, p < 0.00001] and PFS [HR 0.65 95% CI 0.58–0.72, p < 0.00001] benefit of PC was evident in tumors with negative PD-L1 expression. PD-1/PD-L1 inhibitors–chemotherapy combinations were more likely to achieve an objective response than chemotherapy [odds ratio, 1.86; 95% CI, 1.46–2.38, p < 0.00001]. Histologic subtypes and diagnostic assays did not modify the OS and PFS treatment effects for PC compared to chemotherapy.Conclusion: Tumors harboring < 1% PD-L1 expression are likely to benefit from PD-1/PD-L1 inhibitor–chemotherapy regimens in advanced NSCLC.