Sequential HER2-targeted antibody-drug conjugate therapy for acquired resistance in a 55-year-old male kidney transplant recipient with metastatic urothelial carcinoma: a case report.

Background: Metastatic urothelial carcinoma (mUC) with human epidermal growth factor receptor 2 (HER2) amplification is a highly lethal malignancy, particularly in complex patients. While antibody-drug conjugates (ADCs) are promising, their safety and efficacy in renal transplant recipients maintained on chronic immunosuppression remain largely unexplored. Furthermore, there are a paucity of data regarding the sequential use of different ADCs in this high-risk population. This case highlights its unique clinical importance by demonstrating the feasibility and safety profile of biomarker-driven, sequential ADC therapy for refractory mUC in a transplant recipient. Case Description: A 55-year-old male with a history of end-stage renal disease and a 2019 right kidney transplant presented with recurrent mUC of the right renal pelvis. Genomic profiling revealed HER2 amplification. Maintained on tacrolimus and sirolimus, heinitially received disitamab vedotin (DV). Radiographic response assessment demonstrated a partial response with notable regression of lung metastases, complicated by severe grade III peripheral neurotoxicity. Following transient responses to chemotherapy (cisplatin and gemcitabine) and pembrolizumab, the patient experienced further systemic progression. He was then sequentially treated with fourth-line trastuzumab deruxtecan (T-DXd). Subsequent magnetic resonance imaging (MRI) scans revealed a dramatic response, characterized by marked shrinkage of liver metastases and partial resolution of brain lesions, albeit accompanied by suspected pneumonitis. Throughout these multiline systemic therapies, his renal allograft function remained stable. Conclusions: This case suggests that sequential HER2-targeted ADC therapy utilizing different cytotoxic payloads may offer a clinically viable strategy to manage acquired resistance in mUC. Furthermore, it indicates a potentially manageable safety profile regarding renal allograft function. Further longitudinal follow-up and mature survival data are required to establish whether ADCs can serve as a novel standard of care for this specific patient cohort. Additional research is warranted to formulate optimal treatment strategies and safety guidelines for cancer therapy in transplant recipients.