Network meta-analysis of anti-PD-1/PD-L1 regimens in advanced non-squamous NSCLC without EGFR or ALK alterations

AIM: By 2026, several PD-1/PD-L1 antibodies were approved by FDA, EMA and non-EU Eastern European countries for the first-line therapy in advanced non-squamous non-small cell lung cancer (nsNSCLC) without EGFR mutations or ALK alterations. This study aimed to compare overall (OS) and progression-free (PFS) survival among anti-PD-1/PD-L1-containing regimens and to evaluate the immunotherapy effect modification due to PD-L1 expression. METHODS: A systematic search in MEDLINE and Embase on December 23, 2025 identified 15 Phase III randomized clinical trials involving adults with advanced nsNSCLC treated with therapies containing prespecified anti-PD-1/PD-L1 agents. Bayesian multilevel network meta-regressions with M-splines were estimated for OS and PFS, incorporating covariates for PD-L1 expression (TPS <1% versus ≥1%) and its interaction with the treatment class (anti-PD-1/PD-L1-based regimens versus chemotherapy ± bevacizumab). RESULTS: Regardless of PD-L1 expression, treatments with the highest probability of being the best (SUCRA) by OS are prolgolimab + chemotherapy, pembrolizumab + chemotherapy and cemiplimab + chemotherapy (SUCRA 0.80-0.94), by PFS nivolumab + bevacizumab + chemotherapy and atezolizumab + bevacizumab + chemotherapy (SUCRA 0.91-0.96). The hazard ratio for the interaction between PD-L1-negative status and anti-PD-1/PD-L1-containing therapy was 1.09 (95% CrI, 0.95-1.25) for OS and 1.41 (95% CrI, 1.16-1.71) for PFS. CONCLUSION: For advanced nsNSCLC patients, irrespective of PD-L1 expression, prolgolimab, pembrolizumab or cemiplimab, each combined with chemotherapy, are most efficacious by OS; nivolumab or atezolizumab combined with bevacizumab and chemotherapy demonstrate the highest PFS. PD-L1 expression does not modify the effect of examined immunotherapy options on OS, though the opposite is true for PFS.