Comparative outcomes of first-line PD-1/PD-L1 inhibitors plus chemotherapy for advanced squamous non-small cell lung cancer: a systematic review and network meta-analysis of randomized clinical trials

Background: Head-to-head comparisons between the available first-line regimens with programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors and chemotherapy for advanced squamous non-small cell lung cancer (NSCLC) are lacking. Therefore, we conducted a systematic review and network meta-analysis to identify the optimal first-line regimen with PD-1/PD-L1 inhibitors plus chemotherapy for advanced squamous NSCLC. Methods: A systematic review and network meta-analysis of randomized clinical trials (RCTs) were performed. PubMed, Embase, Web of Science, and the ClinicalTrials.gov databases and major annual conferences were searched. RCTs that compared PD-1/PD-L1 inhibitors plus chemotherapy with chemotherapy alone in patients with advanced squamous NSCLC were eligible for inclusion. Risk of bias was assessed using the Cochrane Risk of Bias Tool (version 2.0), and a funnel plot was used to assess the publication bias. Results: A total of nine RCTs comprising 3,210 patients were included. When combined with chemotherapy, PD-1 inhibitors were superior to PD-L1 inhibitors in terms of overall survival (OS) [PD-1: hazard ratio (HR) 0.70, 95% credible interval (CrI): 0.62 to 0.79; PD-L1: HR 0.82, 95% CrI: 0.71 to 0.94] and progression-free survival (PFS) (PD-1: HR 0.50, 95% CrI: 0.45 to 0.55; PD-L1: HR 0.63, 95% CrI: 0.55 to 0.72). Moreover, the PD-1 inhibitor camrelizumab was the most effective agent in combined therapy for prolonging OS (HR 0.56, 95% CrI: 0.44 to 0.71) and PFS (HR 0.32, 95% CrI: 0.25 to 0.42), followed by the PD-L1 inhibitor sugemalimab (OS: HR 0.61, 95% CrI: 0.43 to 0.86; PFS: HR 0.37, 95% CrI: 0.26 to 0.52). Moreover, the addition of camrelizumab or tislelizumab to chemotherapy was associated with the improved objective response rate (ORR) and a longer duration of response (DoR). Regarding safety, pembrolizumab and camrelizumab were associated with the lowest risk of developing grade 3-5 treatment-related adverse events (TRAEs). Most of the trials were at low risk for bias, and no obvious publication bias was observed in the outcomes. Conclusions: When combined with first-line chemotherapy, camrelizumab has the potential to be a preferred option in patients with advanced squamous NSCLC. This finding might serve as a guideline to aid in the selection of first-line immunotherapy plus chemotherapy strategies for advanced squamous NSCLC.