Protective effect of bevacizumab against interstitial lung disease in non-squamous non-small-cell lung cancer: a nationwide target trial emulation study

PURPOSE: We evaluated the association between bevacizumab use and interstitial lung disease (ILD), 180-day mortality, and venous thromboembolism (VTE) risks in patients with non-squamous non-small-cell lung cancer (NSCLC) receiving first-line platinum-based chemotherapy. METHODS: Using the Japanese Diagnosis Procedure Combination database (2011-2023), we identified patients with stage III-IV non-squamous NSCLC who initiated platinum-based chemotherapy with pemetrexed, with or without bevacizumab. A target trial emulation framework was applied. The primary outcome was ILD requiring corticosteroid treatment within 180 days of chemotherapy initiation. The secondary outcomes included 180-day mortality, mortality within 30 days after ILD onset, and VTE. Propensity score overlap weighting was used to balance the baseline covariates. Fine-Gray models and Cox proportional hazards models were used to estimate subdistribution hazard ratios (SHRs) for ILD and VTE and hazard ratios (HRs) for mortality. RESULTS: Overall, 47,433 patients were analyzed (bevacizumab group: n = 12,101; non-bevacizumab group: n = 35,332). Bevacizumab use was associated with lower risks of ILD [SHR, 0.75; 95% confidence interval (CI), 0.67-0.84], 180-day mortality (HR, 0.61; 95% CI, 0.57-0.66), and mortality within 30 days after ILD (HR, 0.71; 95% CI, 0.57-0.88). The overall VTE risk was similar between the two treatment groups. The main results were consistent across subgroups stratified by the baseline platinum agent, ICI use, age group, and ILD history. CONCLUSION: In patients with advanced non-squamous NSCLC receiving first-line platinum-based chemotherapy, bevacizumab use was associated with lower risks of ILD and short-term mortality, without increased VTE risk.