Real-world pharmacovigilance analysis for antibody drug conjugates (ADCs) in treatment of solid tumor malignancies.

Abstract

e20503 Background: Despite their efficacy in targeted cancer therapy, antibody-drug conjugates (ADCs) come with unique toxicity profiles that may be incompletely captured in their trials for FDA approval. We sought to define real-world toxicity phenotypes across FDA-approved ADCs and to evaluate the effect of payload class, linker chemistry, and target expression on patterns of toxicity with the goal of informing clinically actionable monitoring strategies. Methods: We conducted a disproportionality analysis of FDA Adverse Event Reporting System (FAERS) pharmacovigilance data (Q1 2021–Q1 2024) for six FDA-approved ADCs: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), enfortumab vedotin (EV), mirvetuximab soravtansine (MIRV), tisotumab vedotin (TV), and trastuzumab emtansine (T-DM1). We then calculated reporting odds ratios (RORs) and proportional reporting ratios at the MedDRA preferred-term level using primary suspect reports. Safety signals were then interpreted in the context of payload pharmacology and linker stability. Results: Distinct and reproducible toxicity phenotypes were observed across ADC classes. Among topoisomerase I inhibitor (TOPO1) - based ADCs with cleavable linkers, divergent systemic toxicity profiles emerged. T-DXd (n = 4,845) demonstrated a strong pulmonary toxicity signal, including interstitial lung disease and pneumonitis (ROR = 34.6), and was additionally associated with hematologic toxicity, including neutrophil count decrease (ROR = 9.9) and haematotoxicity (ROR = 8.4). In contrast, SG (n = 2,100) was primarily associated with neutropenic colitis (ROR = 108.0), neutropenia (ROR = 55.7), and neutropenic sepsis (ROR = 404.0). Among MMAE-based ADCs studied, toxicity profiles aligned with target organ expression. EV (n = 2,206) showed disproportionately high rates of cutaneous toxicity (ROR = 55.4) and peripheral neuropathy (ROR = 74.3), while TV (n = 389) exhibited marked ocular surface toxicity (ROR = 470.0). Within the maytansinoid class, class- and linker-specific toxicities were evident. MIRV (n = 474) was associated with significant ocular toxicity (ROR = 466.0), whereas T-DM1 (n = 1,479) showed hepatic microvascular injury, including nodular regenerative hyperplasia (ROR = 267.5) and portal hypertension (ROR = 82.4). Conclusions: ADC toxicity is not class-wide but is instead affected by payload, linker, and target. TOPO1 inhibitor ADCs showed divergent toxicity profiles despite payloads, while MMAE ADCs have toxicities related to target expression in normal tissues. Maytansinoid ADC toxicities were distinct, reflecting both payload-dependent effects (DM4 vs DM1) and target-dependent effects (T-DM1). These findings highlight the need for mechanism-informed toxicity monitoring and tailored supportive care strategies to optimize the therapeutic index of ADCs in oncology practice.