First-line PD-1/PD-L1 inhibitors plus chemotherapy vs. chemotherapy alone in stage IIIB-IV non-squamous NSCLC: an updated meta-analysis of phase 3 RCTs.

BACKGROUND: PD-1/PD-L1 inhibitors combined with chemotherapy (PIC) has significantly reshaped treatment approaches in advanced non-small-cell lung cancer (NSCLC). However, whether PIC provides superior long-term efficacy compared to standard chemotherapy in advanced non-squamous NSCLC (nsqNSCLC) still requires comprehensive analysis using recent data from phase 3 randomized controlled trials (RCTs). METHODS: Relevant studies comparing PIC with chemotherapy in stage IIIB-IV nsqNSCLC were identified through six databases. The key measures of interest were overall survival (OS) and progression-free survival (PFS), while additional endpoints encompassed tumor response and safety. RESULTS: Twelve multicenter phase 3 RCTs including 5,054 participants were analyzed. In comparison to chemotherapy alone, the PIC therapy resulted in significant improvements in both OS (HR: 0.73 [0.68-0.79], P < 0.00001) and PFS (HR: 0.59 [0.55-0.63], P < 0.00001). Survival benefits in both endpoints were consistently greater in the combination arm over a 6-60 month observation period. Stratified analysis revealed that the presence of brain metastases (OS, HR: 0.47; PFS, HR: 0.44) and a PD-L1 expression above 50% (OS, HR: 0.64; PFS, HR: 0.62) were predictive of enhanced efficacy for the combination strategy. Regarding treatment response, patients receiving PIC experienced a prolonged duration of response (HR: 0.57 [0.50-0.65], P < 0.00001) and a markedly increased objective response rate (RR: 1.69 [1.55-1.84], P < 0.00001). Nevertheless, both overall (RR: 1.95 [1.32, 2.87], P = 0.0007) and grade 3-5 immune-mediated adverse events (irAEs) (RR: 2.28 [1.64, 3.18], P < 0.00001) occurred more frequently in the PIC group. CONCLUSIONS: PIC therapy provides significant survival benefits and enhances anti-tumor efficacy in stage IIIB-IV nsqNSCLC, although it carries a higher toxicity burden, including both acute hematologic AEs and potentially chronic irAEs that require continuous clinical monitoring. PROSPERO REGISTRATION ID: CRD420251066166.