Efficacy and safety of PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone in stage IIIB-IV squamous non-small cell lung cancer: a systematic review and meta-analysis of phase 3 randomized controlled trials.

Background: Although programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors plus chemotherapy (PC) has improved outcomes in advanced squamous non-small cell lung cancer (NSCLC), the consistency of survival benefit and the predictive value of PD-L1 expression remain uncertain, particularly following the publication of several recent pivotal phase 3 randomized controlled trials (RCTs). This study aimed to systematically evaluate the efficacy and safety of PC versus chemotherapy alone in patients with stage IIIBIV squamous NSCLC and to assess the predictive value of PD-L1 expression. Methods: PubMed, EMBASE, Web of Science, Scopus, ScienceDirect, and the Cochrane Library were systematically searched up to May 25, 2026. Phase 3 RCTs comparing PC with chemotherapy alone in patients with stage IIIB-IV squamous NSCLC were included. Risk of bias was assessed using the Cochrane tool, and evidence certainty was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Hazard ratios (HRs) were pooled for time-to-event outcomes, and risk ratios (RRs) were calculated for binary outcomes using fixed- or random-effects models according to heterogeneity. Results: Fourteen phase 3 RCTs involving 4,481 patients (2,466 patients in the PC arm and 2,015 patients in the chemotherapy arm) were included. The certainty of evidences ranged from moderate to high. Patients receiving PC demonstrated significantly improved overall survival (OS) {HR: 0.73 [95% confidence interval (CI): 0.67, 0.79], P<0.001} and progression-free survival (PFS) [HR: 0.54 (95% CI: 0.48, 0.60), P<0.001] compared with those treated with chemotherapy alone. OS benefits in the PC group were observed across a follow-up period of 6 to 60 months, while PFS improvement was evident from 6 to 24 months. Subgroup analysis indicated that patients with a PD-L1 expression ≥50% experienced superior survival outcomes with PC. Regarding tumor response, PC was associated with a longer duration of response [HR: 0.48 (95% CI: 0.41, 0.55), P<0.001] and a higher objective response rate [RR: 1.50 (95% CI: 1.40, 1.61), P<0.001]. Safety analysis revealed a higher incidence of total and grade 3-5 immune-related adverse events (irAEs). Clinically important adverse events (AEs) were also increased, including treatment-emergent adverse events (TEAEs)/treatment-related adverse events (TRAEs) leading to discontinuation and TEAEs leading to death, highlighting the need for careful monitoring. Conclusions: PC improves survival and tumor response in stage IIIB-IV squamous NSCLC, particularly in patients with higher PD-L1 expression, but increases irAEs, warranting careful benefit-risk assessment and toxicity monitoring.