Oral Toxicities Secondary to TROP2 and HER2-directed Antibody Drug Conjugates. A Multicenter Retrospective Cohort Study.

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 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 2024-2025. 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=0.04), whereas xerostomia (10.9% vs 6.1%, p=0.31) and dysgeusia (9.8% vs 5.2%, p=0.28) 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 = 0.040). In cases of OM, the trajectory of TROP2-associated OM was more acute than with HER-2-associated OM with earlier onset (p = 0.035) and quicker resolution (p = 0.045).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 = 0.001), compared to xerostomia (n = 8/17; p = 0.471) and dysgeusia (n = 2/15; p = 0.196).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 = 0.039). CONCLUSION: TROP2-directed ADCs are associated with a higher-risk of OM (p=0.040) with earlier onset of toxicities (p=0.035), and greater DR requirements (p=0.039). In contrast, HER2-directed ADCs are associated with more prevalent xerostomia and dysgeusia, a higher overall severity, and later onset but potentially longer duration.