Abstract
Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of metastatic urothelial carcinoma (UC) and renal cell carcinoma (RCC). However, these cancers may exhibit divergent responses to the same immunotherapy. Here, we report a case of a patient with concurrent stage IV urothelial carcinoma (UC) and resected stage III clear cell renal cell carcinoma (ccRCC) of the contralateral kidney who experienced complete remission of UC following treatment with enfortumab vedotin (EV) and pembrolizumab but developed hyperprogression of metastatic RCC. As a result, the decision was made to discontinue ICIs and initiate a combination therapy of Lenvatinib (VEGF receptor inhibitor) and Everolimus (mTOR inhibitor). The patient exhibited a near complete radiographic response of the RCC to this combination therapy, with no significant side effects, and has remained well with minimal residual lung disease 18 months after the onset of hyperprogression in ccRCC. This highlights the role of distinct immune microenvironments in mediating differential responses to immunotherapy in patients with coexisting UC and ccRCC. We underscore the importance of personalized treatment strategies in patients with dual malignancies, particularly when divergent responses to immunotherapy are observed, offering durable responses while avoiding the risks associated with continued immune checkpoint inhibition.