Pharmacovigilance study of the association between peripheral neuropathy and antibody-drug conjugates using the FDA adverse event reporting system

Abstract

Antibody-drug conjugates (ADCs) are among the fastest-growing classes of anticancer drugs, making it crucial to evaluate their potential for causing peripheral neuropathy. We analyzed data from the FAERS database (January 1, 2014, to June 30, 2023) using disproportionality and Bayesian methods. We identified 3076 cases of ADC-associated peripheral neuropathy. Our study revealed significant signals for all ADCs (ROR 1.82, 95% CI 1.76-1.89). ADCs with tubulin-binding payloads showed significant peripheral neuropathy signals (ROR 2.31, 95% CI 2.23-2.40), whereas those with DNA-targeting (ROR 0.48, 95% CI 0.39-0.59) and topoisomerase 1 inhibitor (ROR 0.56, 95% CI 0.48-0.66) payloads exhibited non-significant signals. Signals for peripheral sensory neuropathy were 4.83, 2.44, 2.74, and 2.21 (calculated based on IC₀₂₅) for brentuximab vedotin, trastuzumab emtansine, enfortumab vedotin, and polatuzumab vedotin, while signals for peripheral motor neuropathy were 5.31, 0.34, 2.27, and 0.03, respectively. The median time to onset for all ADCs was 127 days (interquartile range 40-457). Tisotumab vedotin had the highest hospitalization rate at 26.67%, followed by brentuximab vedotin at 25.5%. Trastuzumab emtansine had the highest mortality rate ,with 80 deaths (11.96%) among 669 cases. Based on FAERS database, only ADCs with tubulin-binding payloads exhibited significant peripheral neuropathy signals. Brentuximab vedotin and enfortumab vedotin showed similar profiles for peripheral sensory neuropathy and motor neuropathy. Given the delayed time to onset and potentially poor outcomes, ADC-related peripheral neuropathy warrants significant attention.

Keywords: Antibody–drug conjugates; FAERS database; Peripheral neuropathy; Real-world evidence.

Fig. 1

Process for selecting reports of peripheral neuropathy associated with ADCs from the FAERS database. FAERS Food and drug administration adverse event reporting system, ADC antibody–drug conjugate.

Fig. 2

Peripheral neuropathy signal profiles of different ADCs. ADCs antibody–drug conjugates, BV brentuximab vedotin, TE trastuzumab emtansine, EV enfortumab vedotin, PV polatuzumab vedotin, TV tisotumab vedotin.

Fig. 3

Time to onset of ADC-related peripheral neuropathy. ADC antibody–drug conjugate, BV brentuximab vedotin, TE trastuzumab emtansine, EV enfortumab vedotin, PV polatuzumab vedotin, TV tisotumab vedotin.

Fig. 4

The proportion of deaths, life-threatening events, and hospitalizations for ADC-associated peripheral neuropathy. ADC antibody–drug conjugate, BV brentuximab vedotin, TE trastuzumab emtansine, EV enfortumab vedotin, PV polatuzumab vedotin, TV tisotumab vedotin.