First-Line Enfortumab Vedotin Plus Pembrolizumab in Platinum-Ineligible Urothelial Carcinoma: A Three-Case Series

Locally advanced or metastatic urothelial carcinoma (la/mUC) has a poor prognosis. In routine clinical practice, platinum-based chemotherapy has generally been used as first-line treatment. Enfortumab vedotin plus pembrolizumab (EVP) has recently been introduced as another first-line option; however, patients who are platinum-ineligible, such as those with severe renal dysfunction and/or poor performance status, are often underrepresented in clinical studies, and the optimal systemic therapy for this group remains uncertain. Herein, we report three platinum-ineligible patients with la/mUC who received standard-dose EVP as first-line therapy. Platinum ineligibility was defined as creatinine clearance (CrCl) < 30 mL/min and/or Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 3. In Case 1 (hemodialysis; ECOG PS 1), EVP resulted in improvement of bone metastases and durable disease control, with manageable adverse events (AEs), including grade 2 skin toxicity, dysgeusia, hypothyroidism, and transient peripheral sensory neuropathy that resolved after temporary treatment interruption. In Case 2 (CrCl 23.1 mL/min; ECOG PS 2), EVP induced a partial response in the bladder and nodal lesions; however, treatment was complicated by early-onset grade 4 immune-related nephritis requiring high-dose corticosteroids. Best supportive care was adopted at progression. In Case 3 (ECOG PS 3), rapidly progressive renal pelvic la/mUC showed early disease progression with spinal cord compression despite EVP, leading to the patient being transitioned to best supportive care. Across all three cases, no life-threatening toxicity was clearly attributable to enfortumab vedotin. These observations suggest that standard-dose EVP may be a feasible first-line option for carefully selected platinum-ineligible patients, when administered with close monitoring, flexible dose adjustment, and prompt management of immune-related and other AEs.