Oral toxicities secondary to TROP2 and HER2-directed antibody drug conjugates: a multicenter retrospective cohort study

Abstract

Abstract Purpose The aim of this multicenter retrospective cohort study was to characterize the incidence, clinical presentation, timing, severity, and management of oral toxicities (OTs) associated with TROP2-directed (datopotamab deruxtecan and sacituzumab govitecan) and HER2-directed (trastuzumab deruxtecan) antibody-drug conjugates in patients with advanced-stage cancers. Methods A retrospective medical-records review of 207 patients was conducted to characterize antibody–drug conjugate (ADC)-associated OTs. Patients had been treated for advanced-stage cancers treated with TROP2 (sacituzumab govitecan and datopotamab deruxtecan) and HER2-directed ADCs (trastuzumab deruxtecan) at the Sapienza University–Hospital and Miami Cancer Institute between 2024 and 2025. Multivariate logistic regressions were performed to evaluate any correlation between the ADC type and prevalence, type, severity, time of onset, and time to resolution of OTs. Results Overall, 47 patients (22.7%) developed OTs, with a median onset time of 7.5 days (range: 1-358). The OT prevalence was similar between TROP2 (n = 27, 23.5%) and HER2-directed (n = 20, 21.7%) ADCs, however, oral mucositis (OM) was more frequent with TROP2-directed ADCs (14.8% vs 5.4%, P = .04), whereas xerostomia (10.9% vs 6.1%, P = .31) and dysgeusia (9.8% vs 5.2%, P = .28) were more common and more severe with HER2-directed ADCs, although not reaching statistical significance. Patients receiving TROP2-directed ADCs had a 3.02-fold higher-risk of developing OM compared to those receiving HER2-directed ADCs (95% CI: 1.07-8.52, P = .040). In cases of OM, the trajectory of TROP2-associated OM was more acute than with HER-2-associated OM with earlier onset (P = .035) and quicker resolution (P = .045). Management of OTs was provided for 29 (14.0%) patients with the majority of them receiving TROP2-directed ADCs (n = 21, 17.3%). With regard to OTs, patients developing OM were associated with a greater need for management (n = 19/22; P = .001), compared to xerostomia (n = 8/17; P = .471) and dysgeusia (n = 2/15; P = .196). Ultimately, ADC dose reduction (DR) was required in 43 patients (20.8%) and was significantly more frequent with TROP2-directed ADCs (26.1% vs 14.1%, P = .039). Conclusion TROP2-directed ADCs are associated with a higher-risk of OM (P = .040) with earlier onset of toxicities (P = .035), and greater DR requirements (P = .039). In contrast, HER2-directed ADCs are associated with more prevalent xerostomia and dysgeusia, a higher overall severity, and later onset but potentially longer duration.