Objectives: Use of immune checkpoint inhibitors (ICIs) as first-line treatment for advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) remains controversial. Clinical trials comparing single-drug immunotherapy (IO) with immunotherapy plus chemotherapy (IC) are lacking. We aimed to compare the efficacy of IO alone with that of IC as first-line treatment for advanced NSCLC.

Design: Systematic review

Data sources: PubMed, the Cochrane Library, and Embase for related studies on NSCLC; ClinicalTrials.gov, American Society of Clinical Oncology Meeting Library, and World Conference on Lung Cancer for relevant conference abstracts.

Eligibility criteria: Articles meeting the following criteria were selected: (1) randomized controlled trials on NSCLC treatment, (2) all individuals in the studies had not received treatment previously, and (3) research on IO monotherapy using programmed death-1/programmed death ligand-1 (PD-L1) inhibitors or IC.

Data extraction and synthesis: After reading the original literature, two reviewers independently extracted the relevant information. The primary outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). We also extracted data on treatment-related adverse events and immune-related adverse events (irAEs).

Results: Overall, 10 randomized controlled clinical trials (n = 5765) were included. As first-line treatment for advanced NSCLC, IC tended to yield better PFS, OS, and ORR than did IO. Furthermore, IC yielded significantly better PFS than IO when tumor PD-L1 expression was at least 50% (HR: 1.81, 95% CI: 1.18–2.78) and yielded a better OS and PFS when tumor PD-L1 expression was at least 1%; IO resulted in fewer adverse events than did IC. However, the incidence of irAEs was higher for IO than for IC.

Conclusions: The findings of the indirect comparison indicate that IC as first-line treatment for advanced NSCLC is significantly more effective than IO in patients with PD-L1 expression in at least 50% of tumor cells.