Systemic Inflammation Modifies the Efficacy of Bevacizumab Added to Atezolizumab Plus Chemotherapy for Advanced Non‐Squamous Non‐Small Cell Lung Cancer: A Multicenter Retrospective Study

INTRODUCTION: Bevacizumab, an anti-VEGF antibody, inhibits angiogenesis and modulates the tumor microenvironment. Because systemic inflammation is linked to VEGF activation and immune modulation, it may affect bevacizumab efficacy. However, this relationship remains unclear. We therefore evaluated whether systemic inflammation, assessed via the serum C-reactive protein (CRP) level, modifies survival benefit when adding bevacizumab to chemoimmunotherapy in advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed patients with advanced non-squamous NSCLC from 13 Japanese institutions receiving first-line atezolizumab plus chemotherapy with or without bevacizumab between December 2018 and December 2022. The primary endpoint was overall survival (OS). The interaction between CRP level (< 1 mg/dL vs. ≥ 1 mg/dL) and bevacizumab treatment was evaluated, and sensitivity analyses were performed to confirm the robustness of our findings. RESULTS: Among 193 eligible patients, 109 (56.5%) received bevacizumab. With a median follow-up of 44.2 months, the median OS was 24.5 months in patients with low CRP and 17.3 months in those with high CRP (log-rank test for trend, p = 0.04). Bevacizumab significantly improved OS in patients with high CRP (hazard ratio [HR] 0.63; 95% confidence interval, 0.40-0.99; p = 0.04), but not in those with low CRP (HR 1.22; p = 0.50). The interaction between CRP level and bevacizumab treatment was significant (p = 0.033). Sensitivity analyses supported these results. CONCLUSIONS: Systemic inflammation, as assessed by CRP level, may modify the efficacy of bevacizumab in advanced non-squamous NSCLC. These hypothesis-generating findings warrant prospective validation to clarify the role of CRP in treatment stratification.