A multi-database pharmacovigilance study reveals distinctive immunosuppressive and opportunistic infection disproportionality signals with bevacizumab and temozolomide combination therapy in glioblastoma.

Background: Bevacizumab (BEV) plus temozolomide (TMZ) is increasingly used for glioblastoma, yet the immunosuppression-related adverse event spectrum and safety signals of this combination-including potential interaction effects and time-to-onset patterns-have not been comprehensively characterized in real-world pharmacovigilance data. Methods: A retrospective analysis was conducted using FAERS and CVARD; a multi-algorithm framework (Omega shrinkage model, PRR, and ROR) was applied for signal detection, and interaction analyses were conducted to explore potential drug-drug interaction signals (more-than-additive reporting disproportionality patterns) in spontaneous reporting data; the Weibull model was used to evaluate time-dependent onset-hazard patterns based on TTO, and multivariate logistic regression was performed to identify factors associated with IRAE reporting. Results: A total of 1,076 reports in the BEV + TMZ combination therapy group, 2,633 reports in the BEV monotherapy group, and 3,156 reports in the TMZ monotherapy group were included. The combination regimen exhibited a unique IRAEs profile, showing strong reporting disproportionality signals for rare but serious immunosuppressive and opportunistic infection events, including hemophagocytic lymphohistiocytosis (HLH; Conclusion: BEV + TMZ combination therapy shows disproportionality signals for severe immunosuppression and opportunistic infections. These signal patterns, including time-to-onset distributions, may help prioritize clinical vigilance and hypothesis generation, but do not estimate incidence or establish causality and require prospective confirmation.