The benefits and risks of adding PD-1/PD-L1 inhibitors to chemotherapy for stage IIIb-IV non-small-cell lung cancer: an updated meta-analysis based on phase 3 randomized controlled trials

Abstract

Background: Previous research has confirmed that integrating PD-1/PD-L1 inhibitors with chemotherapy (PC) represents a more effective strategy for treating advanced non-small-cell lung cancer (NSCLC). However, with the increasing number of phase 3 randomized controlled trials (RCTs) published in recent years, it is essential to re-evaluate the validity of this conclusion and to comprehensively assess the efficacy and safety across diverse patient subgroups. Methods: We systematically reviewed phase 3 RCTs comparing PC with chemotherapy alone for stage IIIb-IV NSCLC. Data were extracted and analyzed for overall survival (OS), progression-free survival (PFS), response rates, and adverse events (AEs). Subgroup analyses were performed based on factors such as disease stage, pathological type, etc. Results: After screening, 19 phase 3 RCTs involving 9335 patients were included. Our updated analysis confirmed at PC therapy significantly improves OS (hazard ratio [HR]: 0.73 [0.69, 0.77], P < 0.00001), PFS (HR: 0.56 [0.52, 0.60], P < 0.00001), duration of response (DOR, HR: 0.50 [0.45, 0.54], P < 0.00001) and objective response rate (ORR, risk ratio [RR]: 1.59 [1.51, 1.67], P < 0.00001) compared to chemotherapy alone. The survival benefits were consistent across all subgroups and increases with longer follow-up. Brain metastases and PD-L1 combined positive score (CPS) > 50% were the favorable factors for PC group. However, the combined treatment was associated with an increased incidence of total/grade 3–5 treatment emergent AEs (TEAEs), and immune-related AEs (irAEs), although the overall safety profile remained manageable. The most common AEs in the PC group were blood toxicity related AEs (anemia, neutrophil count decreased, etc). Conclusion: The PC therapy continues to provide a substantial survival benefit for patients with stage IIIb-IV NSCLC. However, its higher incidence of AEs, especially irAEs, needs to be taken seriously. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251005925, identifier CRD420251005925.