Efficacy and safety of chemotherapy plus immunotherapy in unresectable stage III–IV non-small cell lung cancer, with analysis of the additional role of anti-angiogenic agents

Purpose: Chemo-immunotherapy has demonstrated significant survival benefits in non-small cell lung cancer. However, real-world data on its effectiveness and safety in patients with unresectable stage III-IV disease remain insufficient. Furthermore, whether the addition of anti-angiogenic agents provides additional benefit beyond chemo-immunotherapy remains unclear. This study aimed to evaluate the real-world effectiveness and safety of adding immune checkpoint inhibitors to chemotherapy, and to further explore the added value of anti-angiogenic therapy. Methods: A total of 260 patients with unresectable stage III/IV NSCLC treated at two centers (2018-2025) were enrolled. Patients were divided into a chemotherapy-based immunotherapy group (n=162) and a non-immunotherapy chemotherapy group (n=98); the former was further stratified by the addition of anti-angiogenic therapy (n=71) or not (n=91). To address baseline imbalances between groups, propensity score matching (PSM) (1:1 nearest-neighbor, caliper=0.2 SD) was performed using key covariates. Progression-free survival and overall survival were assessed using Kaplan-Meier analysis and Cox regression. Adverse events were graded per CTCAE 5.0. Results: Chemotherapy-based immunotherapy significantly prolonged median PFS (9.0 vs 6.8 months, P<0.001) and OS (22 vs 14.2 months, P = 0.028) compared with non-immunotherapy chemotherapy regimens. This regimen was independently associated with improved PFS (HR = 0.56, P<0.001) and OS (HR = 0.65, P = 0.018). Conversely, ECOG PS 2 was a strong independent predictor of worse prognosis (PFS: HR = 6.45; OS: HR = 5.50, both P<0.001). Among recipients of chemotherapy‑based immunotherapy, adding anti-angiogenic therapy further improved PFS (9.1 vs 6.8 months, P = 0.044; HR = 0.69, P = 0.060), with no significant increase in adverse events (P > 0.05). Conclusions: Chemoimmunotherapy significantly improved PFS and OS in unresectable stage III/IV NSCLC. The addition of anti-angiogenic agents to this backbone further prolonged PFS without increasing adverse events.