A recent pharmacovigilance study published in Scientific Reports has shed light on the association between antibody-drug conjugates (ADCs) and peripheral neuropathy (PN). The study, leveraging data from the FDA Adverse Event Reporting System (FAERS) database, reveals that ADCs with tubulin-binding payloads are significantly linked to PN, with variations in onset time and severity observed among different ADC therapies. This real-world analysis underscores the importance of vigilant monitoring and risk management for patients undergoing ADC treatment.
ADC Payloads and Peripheral Neuropathy
The study, which analyzed nearly 40 million adverse event reports from January 2014 to June 2023, identified 3,076 reports related to PN following ADC administration. The data revealed that tubulin-binding agents were most strongly associated with PN (IC025 1.15; ROR025 2.23), particularly enfortumab vedotin (IC025 1.50; ROR025 2.87). In contrast, ADCs with DNA-targeting or topoisomerase 1 inhibitor payloads did not show a significant association with PN.
Disparities in Toxicity Profiles
Further analysis revealed differences in the toxicity profiles of ADCs with tubulin-binding payloads. Brentuximab vedotin showed the broadest spectrum of PN adverse events (AEs), while enfortumab vedotin exhibited the strongest signal for PN (IC025 4.13). Trastuzumab emtansine, on the other hand, was associated with the highest mortality rate (11.96%) among the examined ADCs, despite a relatively low signal intensity for PN in the study.
Time to Onset and Clinical Outcomes
The median time to onset (TTO) of ADC-related PN was 127 days (IQR 40–457). Individual ADCs showed varying TTOs, with polatuzumab vedotin having the shortest median TTO of 23 days (IQR 7–56) and brentuximab vedotin having a median TTO of 56 days (IQR 20–195). Hospitalization rates were highest for tisotumab vedotin-induced PN (26.67%), while brentuximab vedotin-related PN had a hospitalization rate of 25.5%.
Mechanisms and Implications
The study highlights that the toxicity of ADCs is often linked to the payload. Tubulin-inhibiting agents like monomethyl auristatin E (MMAE), found in several ADCs, can cause PN due to peripheral axonopathy. The release of free payload into systemic circulation and off-target delivery to healthy cells contribute to this toxicity. The researchers emphasize that monitoring and follow-up are crucial due to the delayed TTO and potential for poor outcomes.
Study Limitations
The authors acknowledge several limitations, including the use of a spontaneous reporting system (SRS), which does not allow for direct safety comparisons or incidence rate calculations. The data may also suffer from confounding issues due to the lack of baseline characteristics. Additionally, the high proportion of reports for brentuximab vedotin may introduce bias. Despite these limitations, the study provides valuable insights into ADC-associated PN and guides future research in this area.
