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

## TL;DR

This study finds that combining bevacizumab and temozolomide for glioblastoma is linked to rare but serious immune-related side effects and infections.

## Contribution

The study identifies unique immunosuppressive and opportunistic infection signals in real-world data for a glioblastoma drug combination.

## Key findings

- The combination of bevacizumab and temozolomide shows strong signals for rare immune-related adverse events like hemophagocytic lymphohistiocytosis and strongyloidiasis.
- Drug interaction analysis suggests synergistic toxicity effects in the combination therapy beyond additive effects of monotherapies.
- The combination therapy alters the time-to-onset patterns for some adverse events, such as lymphocytopenia.

## Abstract

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.

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.

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; Ω = 0.648), strongyloidiasis (Ω = 0.744), Epstein–Barr virus infection (Ω = 0.580), and cytomegalovirus pneumonitis (Ω = 0.943). Drug interaction analysis suggested potential interaction signals between BEV and TMZ in spontaneous reporting data, with markedly elevated PRR/interaction ORs for hematological (e.g., pancytopenia) and non-hematological toxicities (e.g., enteritis), exceeding the additive effect expected from the two monotherapies in spontaneous reporting data. Temporal dynamic analysis indicated that combination therapy altered the time-to-onset pattern for some events; for instance, the median time to onset for lymphocytopenia shifted from 34 days (BEV monotherapy) to 23 days, and the onset-hazard pattern shifted from an increasing type to a decreasing type. Multivariable logistic regression adjusting for sex, age group, body-weight group, and reporter type showed higher odds of IRAE reporting for BEV monotherapy versus TMZ monotherapy (OR = 3.6037, 95% CI: 1.0378–12.652, p < 0.05), while the overall IRAE reporting odds for BEV + TMZ were not significantly different from TMZ (OR = 2.9677, 95% CI: 0.5018–15.2056, p = 0.1988) or BEV (OR = 0.8235, 95% CI: 0.1454–4.6642, p = 0.8263).

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.