Spychalla, Megan

Abstract Enfortumab vedotin (EV), pembrolizumab, and EV plus pembrolizumab (EV/P) have rapidly reshaped the treatment landscape of advanced urothelial carcinoma, but toxicity increasingly determines treatment delivery, treatment continuity, and real-world benefit. As EV/P moves into broader clinical use, clinicians must distinguish adverse events related to antibody-drug conjugate exposure from immune-mediated toxicities and recognize syndromes in which both mechanisms may contribute. In this practical, mechanism-informed review, we synthesize pivotal trials, mature follow-up reports, and representative real-world cohorts describing the safety of EV monotherapy, pembrolizumab monotherapy, and EV/P in urothelial carcinoma. Because adverse-event reporting and ascertainment are heterogeneous across studies, including differences in preferred terms, composite categories, grading frameworks, and treatment-related versus all-cause reporting, we emphasize clinically interpretable patterns rather than pooled estimates. EV monotherapy is characterized by cutaneous toxicity, peripheral neuropathy, hyperglycemia, dysgeusia, and ocular events, including early epithelial/metabolic events and cumulative neuropathy. Pembrolizumab monotherapy has a lower overall high-grade toxicity burden but is defined by immune-mediated endocrinopathies, pneumonitis, hepatitis, colitis, and nephritis. Combination therapy produces a predictable overlap of these toxicity domains, creating diagnostic and management challenges for syndromes such as skin toxicity, diarrhea, fatigue, and pulmonary symptoms. We provide comparative visual toxicity signatures, regimen-specific summary tables, temporal toxicity mapping, and a pragmatic attribution framework that classifies events as EV-predominant, immune-predominant, overlap/indeterminate, or high-risk requiring initial interruption of both agents. This review aims to support bedside recognition, provisional attribution, early management, and safer implementation of EV/P in contemporary urothelial carcinoma practice.

Aim: Despite advances with immune checkpoint inhibitor (ICI)-based regimens in the past decade, patients with metastatic urothelial cancer (mUC) face a poor prognosis with few approved options. Platinum-based chemotherapy with paclitaxel and carboplatin (TC) +/– ICI may be a feasible choice. Methods: We generated an IRB-approved, HIPAA-compliant retrospective database of patients at Mayo Clinic Cancer Center with mUC who started TC +/– ICI after disease progression on ICI from January 2018 through December 2024. Baseline demographics, clinicopathologic features, and treatment outcomes were extracted from the electronic health record. Kaplan-Meier method was used to calculate median duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: There were 32 patients who fit inclusion criteria, including 31 patients who had disease progression on ICI in the metastatic setting and 1 patient who developed metastatic disease on adjuvant nivolumab. Patients received a median of 4 cycles (range 1–14) of TC over median 12 weeks (range 3–53). Overall, 81% of patients received TC concurrently with an ICI, and 28% continued maintenance ICI after TC discontinuation (at the treating oncologist’s discretion due to adequate response or toxicity). The best objective response rate was 41% and disease control rate was 75%, with median DOR of 4.8 months (IQR 2.7–10.4), median PFS of 4.6 months (IQR 3.3–10.2), and median OS of 9.4 months (IQR 6.3–15.9). Some patients in this series had very durable responses with PFS > 12 months and OS > 24 months. TC +/– ICI was overall well tolerated with expected type and severity of adverse events. Conclusions: Strategies to overcome ICI resistance are needed, and TC +/– ICI after disease progression on an ICI shows promising tolerability and efficacy in this setting for patients with mUC. Our series was notable for some patients having a durable response. Validation in larger cohorts is warranted.