Comparative pharmacovigilance analysis of adverse events associated with zanidatamab versus trastuzumab using the FDA Adverse Event Reporting System.

Abstract

e23383 Background: Zanidatamab, a bispecific antiHER2 antibody, has demonstrated promising activity in HER2 expressing malignancies including breast cancer, but its postmarketing safety profile relative to trastuzumab is not well defined. Spontaneous reporting systems such as the FDA Adverse Event Reporting System (FAERS) enable hypothesis generating comparisons of adverse event (AE) disproportionality between agents targeting the same pathway. Methods: We conducted a retrospective disproportionality analysis of FAERS reports listing zanidatamab or trastuzumab as suspect drugs. We identified 182 zanidatamab reports (2022–2026) and 80,579 trastuzumab reports (1998–2026). Adverse events were grouped using MedDRA and for predefined AEs of clinical and mechanistic interest, 2×2 contingency tables were constructed, reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated, and two-sided Fisher’s exact tests assessed statistical significance. Results: Compared with trastuzumab, zanidatamab showed higher disproportional reporting of gastrointestinal, renal, and cardiovascular events, with strong enrichment for diarrhea (ROR 4.16, 95% CI 3.01–5.74; p < 0.001) and infusion-related reactions (ROR 9.85, 95% CI 6.23–15.59; p < 0.001). Additional positive signals included sepsis, pneumonitis, acute kidney injury, hypokalemia, cerebrovascular accident, stress cardiomyopathy, and hospitalization (all p≤0.006). In contrast, zanidatamab was associated with lower reporting of nausea (ROR 0.41, 95% CI 0.18–0.93; p = 0.024), death (ROR 0.32, 95% CI 0.12–0.86; p = 0.015), and neutropenia (ROR 0.17, 95% CI 0.02–1.18; p = 0.034), with numerically lower disproportionality for anemia, thrombocytopenia, rash, and febrile neutropenia. Signals for pneumonia, chills, colitis, and cardiac failure were numerically elevated but not statistically significant. Conclusions: In our study, zanidatamab demonstrated a distinct AE profile compared with trastuzumab, with higher reporting of diarrhea, infusion related reactions, sepsis, pneumonitis, acute kidney injury, and select cardiovascular and cerebrovascular events, alongside lower disproportional reporting of nausea, death, and some hematologic toxicities. This analysis is subject to the inherent limitations of spontaneous reporting, unknown exposure denominators and the relatively small number of zanidatamab reports reflecting its recent regulatory approval and shorter duration of real-world exposure. Prospective pharmacovigilance studies are needed to validate these signals and refine zanidatamab’s risk-benefit profile.