Urothelial carcinoma (UC) is predominantly a disease of older adults. Many patients with locally advanced or metastatic UC have impaired renal function, poor performance status, or clinically relevant comorbidities, which often limit the use of platinum-based chemotherapy. Although immune checkpoint inhibitor monotherapy has shown antitumor activity in cisplatin-ineligible patients with advanced UC, previous studies mainly addressed cisplatin-ineligible rather than strictly platinum-ineligible populations (1, 2). A real-world analysis by Pond et al. specifically evaluated platinum-ineligible patients treated with first-line programmed cell death protein 1/programmed death-ligand 1 inhibitors and highlighted the poor outcomes and clinical relevance of this underrepresented population (3). Platinum-ineligible patients therefore represent a particularly vulnerable population with limited therapeutic options and unmet clinical needs.

Enfortumab vedotin plus pembrolizumab (EVP) has substantially changed the first-line treatment landscape for locally advanced or metastatic UC. Early-phase studies demonstrated promising antitumor activity and manageable safety of EVP in patients with previously untreated advanced UC, including cisplatin-ineligible patients (4, 5). Subsequently, the phase III EV-302/KEYNOTE-A39 trial showed that first-line EVP significantly improved progression-free survival (PFS) and overall survival (OS) compared with platinum-based chemotherapy, establishing EVP as a new standard first-line treatment (6).

However, evidence supporting EVP in platinum-ineligible patients remains limited. In EV-302, key eligibility criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and adequate renal function, defined as measured or calculated creatinine clearance (CrCl) ≥30 ml/min. Patients with ECOG PS 2 also had to meet additional hematologic, renal, and cardiac criteria. Thus, patients with CrCl <30 ml/min, ECOG PS ≥3, or poor PS combined with renal impairment were not adequately represented in this pivotal trial. Consequently, the real-world clinical course, tolerability, and outcomes of first-line EVP in platinum-ineligible patients remain insufficiently characterized.

In this retrospective single-center study, we described the clinical course of platinum-ineligible patients treated with first-line EVP within a consecutive real-world cohort of patients with locally advanced or metastatic UC.

Study design and patients. This retrospective single-center study included consecutive patients with locally advanced or metastatic UC who initiated first-line EVP at Saitama Medical University International Medical Center between December 2024 and March 2026. Overall, 40 patients were included. At EVP initiation, patients were categorized as platinum eligible or platinum ineligible using prespecified CrCl-based criteria adapted from Pond et al. (3). The present analysis focused on the clinical course of platinum-ineligible patients within this consecutive real-world cohort.

Data collection. Clinical and laboratory data were retrospectively extracted from medical records. Baseline variables at EVP initiation included age, sex, body weight, serum creatinine level, ECOG PS, primary tumor site, histological subtype, history of prior radical treatment, metastatic sites, neutrophil count, lymphocyte count, hemoglobin level, and C-reactive protein level. CrCl was calculated using the Cockcroft-Gault equation based on age, body weight, sex, and serum creatinine level (7). The neutrophil-to-lymphocyte ratio (NLR) was calculated by dividing the neutrophil count by the lymphocyte count. NLR, hemoglobin level, and C-reactive protein levels were included as exploratory clinical variables because they are readily available markers that may reflect systemic inflammation, anemia, tumor burden, and general condition in routine clinical practice.

Assessment of platinum eligibility. Patients were classified as platinum ineligible if they met any of the following criteria: CrCl <30 ml/min, ECOG PS ≥3, or ECOG PS 2 with CrCl 30-59 ml/min. Patients who did not meet any of these criteria were classified as platinum eligible. For descriptive purposes, platinum-eligible patients were further categorized as cisplatin eligible or carboplatin eligible according to the Galsky criteria (8).

Outcome measures. Tumor response was assessed radiologically according to the Response Evaluation Criteria in Solid Tumors version 1.1 (9). Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (10). The outcomes of interest were objective response rate (ORR), PFS, OS, treatment-related AEs, and individual treatment courses, with particular focus on platinum-ineligible patients. ORR was defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) as their best overall response. PFS was defined as the time from EVP initiation to radiographic or clinical disease progression or death from any cause. OS was defined as the time from EVP initiation to death from any cause. Individual treatment courses were visualized using a swimmer plot.

Statistical analysis. Clinical outcomes were analyzed descriptively, with particular focus on platinum-ineligible patients. Baseline characteristics and treatment outcomes were summarized according to platinum eligibility. Categorical variables were compared using Fisher’s exact test or the chi-square test, as appropriate, and continuous variables were compared using the Mann-Whitney U test. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate Cox proportional hazards regression analyses were performed as exploratory analyses to identify factors associated with PFS and OS. Because of the small number of platinum-ineligible patients and limited number of events, survival comparisons and Cox regression analyses were considered exploratory and hypothesis-generating. A two-sided p value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS Statistics version 31.0 (IBM Corp., Armonk, NY, USA).

Ethics. This study was approved by the Institutional Review Board of Saitama Medical University International Medical Center (approval No. 24-031) and was conducted in accordance with the Declaration of Helsinki. All patients had provided written comprehensive consent for the use of anonymized clinical data for research and publication purposes, and an opt-out opportunity was provided through study information disclosure. The requirement for additional written informed consent was waived by the Institutional Review Board.

Patient characteristics. A total of 40 consecutive patients who received first-line EVP were included. Of these, 32 patients (80.0%) were classified as platinum eligible and eight patients (20.0%) as platinum ineligible. Among the platinum-eligible patients, six were cisplatin eligible and 26 were carboplatin eligible.

Baseline characteristics according to platinum eligibility are shown in Table I. Median age and the proportion of male patients were similar between the platinum-eligible and platinum-ineligible groups. ECOG PS differed significantly between the groups (p=0.007), reflecting the criteria used to define platinum ineligibility. No significant differences were observed in primary tumor site, histological subtype, prior radical treatment, or metastatic distribution. Median creatinine clearance was lower in the platinum-ineligible group than in the platinum-eligible group (33.7 ml/min vs. 47.1 ml/min; p=0.030). Neutrophil-to-lymphocyte ratio, hemoglobin level, and C-reactive protein level were similar between the groups.

Tumor response. Tumor response was evaluable in 33 patients, including 27 platinum-eligible and six platinum-ineligible patients. Seven patients without radiological response assessment were excluded from the response analysis. Best overall response according to platinum eligibility is summarized in Table II In the platinum-ineligible subgroup, CR, PR, stable disease, and progressive disease were observed in one (16.7%), three (50.0%), one (16.7%), and one (16.7%) patient, respectively. The ORR in the platinum-ineligible subgroup was 66.7%. In the platinum-eligible group, CR, PR, stable disease, and progressive disease were observed in six (22.2%), 12 (44.4%), three (11.1%), and six (22.2%) patients, respectively.

Survival outcomes. Kaplan-Meier estimates of PFS are shown in Figure 1. In the overall cohort, the median PFS was 10.4 months [95% confidence interval (CI)=4.1-16.6] (Figure 1A). When described according to platinum eligibility, the median PFS was 10.4 months (95% CI=4.4-16.4) in the platinum-eligible group and was not reached in the platinum-ineligible subgroup (Figure 1B).

Kaplan-Meier estimates of OS are shown in Figure 2. In the overall cohort, the median OS was 12.9 months (95% CI=9.4-16.4) (Figure 2A). The median OS was 12.6 months (95% CI=9.4-15.8) in the platinum-eligible group and was not reached in the platinum-ineligible subgroup (Figure 2B). Because only eight patients were platinum ineligible, survival outcomes according to platinum eligibility should be interpreted descriptively.

Exploratory predictors of survival. Exploratory univariate Cox proportional hazards regression analyses were performed for PFS and OS. In these exploratory analyses, inflammatory and disease burden-related factors, including C-reactive protein level and liver metastases, were associated with survival outcomes. Because of the small number of patients and events, these findings should be interpreted cautiously.

Safety. Selected treatment-related AEs are summarized in Table III. In the overall cohort, the most common any-grade treatment-related AEs were skin toxicity in 29 patients (72.5%), dysgeusia in 20 (50.0%), and fatigue in 14 (35.0%). In the platinum-ineligible subgroup, any-grade skin toxicity, dysgeusia, and fatigue occurred in four (50.0%), six (75.0%), and four (50.0%) patients, respectively. In the platinum-eligible group, these events occurred in 25 (78.1%), 14 (43.8%), and 10 (31.3%) patients, respectively.

The incidence of grade ≥3 treatment-related AEs was low in the platinum-ineligible subgroup. Grade ≥3 skin toxicity occurred in one platinum-ineligible patient (12.5%), and no grade ≥3 hyperglycemia was observed in this subgroup. Overall, no apparent increase in severe treatment-related toxicity was observed among the selected platinum-ineligible patients in this small cohort.

Treatment course. Individual treatment courses are shown in Figure 3. The swimmer plot demonstrated substantial interpatient heterogeneity in treatment duration and clinical trajectories after initiation of first-line EVP. Some patients discontinued EVP early because of progressive disease or AEs, whereas others achieved a response and maintained disease control for a prolonged period, either during continued EVP treatment or after transition to a treatment-free interval. Subsequent systemic therapy was administered in selected patients after disease progression or treatment discontinuation. Prolonged treatment exposure or sustained disease control was also observed in selected platinum-ineligible patients, suggesting that clinical benefit from first-line EVP may be achievable in this population.

In this retrospective single-center study, selected platinum-ineligible patients with locally advanced or metastatic UC showed objective responses and acceptable tolerability after first-line EVP. Among six response-evaluable platinum-ineligible patients, one achieved CR and three achieved PR. Severe treatment-related AEs were infrequent in this subgroup. Because only eight patients were classified as platinum ineligible, these findings should be interpreted as descriptive and hypothesis-generating rather than as definitive evidence of efficacy or safety in this population.

Platinum-ineligible patients have historically had poor outcomes. In a large U.S. real-world database study conducted before the widespread use of first-line EVP, Gupta et al. reported that platinum-ineligible patients accounted for 11% of patients with advanced UC receiving first-line treatment (11). These patients were less likely to receive platinum-based chemotherapy and exhibited inferior survival outcomes compared with platinum-eligible patients, with median OS of 5.1 and 13.3 months, respectively. Thus, more effective treatment strategies are needed in this vulnerable population.

EVP has substantially altered the therapeutic landscape of first-line treatment for advanced UC. In the EV-302/KEYNOTE-A39 trial, EVP significantly improved PFS and OS compared with platinum-based chemotherapy (6). However, patients with severe renal dysfunction, ECOG PS ≥3, or poor PS combined with renal impairment were not adequately represented. Therefore, the real-world clinical course, tolerability, and outcomes of first-line EVP in truly platinum-ineligible patients remain insufficiently characterized.

Historically, platinum eligibility has been a central criterion for treatment selection in advanced UC. In the contemporary era of first-line EVP therapy, however, platinum eligibility alone may not adequately characterize treatment suitability. EVP has a distinct efficacy and toxicity profile that differs from platinum-based chemotherapy. Therefore, treatment decisions should incorporate frailty, vulnerability, organ function, tumor burden, comorbid conditions, and the feasibility of close monitoring and early toxicity management.

Our study adds to emerging real-world evidence in this setting. Litt et al. reported that OS, PFS, and enfortumab vedotin interruption-free survival did not differ significantly between patients with CrCl <30 ml/min and those with CrCl ≥30 ml/min (12). Similar findings were also reported in a recent Japanese multicenter study by Kobari et al., in which renal function was not independently associated with inferior oncologic outcomes during EV monotherapy (13). These observations further support the feasibility of administering EV-based therapy in selected patients with renal dysfunction when appropriate monitoring and toxicity management are implemented. However, these studies focused primarily on renal function, whereas the present study used a prespecified CrCl-based definition of platinum ineligibility incorporating both renal function and ECOG PS. Therefore, our cohort may better reflect the clinically heterogeneous population encountered in routine practice.

Published experience with first-line EVP in platinum-ineligible patients remains scarce. Recently, Nakamura et al. evaluated the outcomes of EV monotherapy in patients who were ineligible for the EV-301 trial. Although their treatment setting differed from the present first-line EVP setting, their study showed clinically meaningful antitumor activity and manageable safety in patients with poorer baseline characteristics, including impaired renal function and poor PS (14).

These findings suggest that carefully selected EV-301 trial-ineligible or clinically vulnerable patients may still benefit from EV-based treatment. Our findings extend this concept to the first-line EVP setting by specifically evaluating platinum-ineligible patients treated in routine clinical practice. To our knowledge, only four cases of first-line EVP in platinum-ineligible patients have been reported: one hemodialysis patient described by Mizuno et al. and three platinum-ineligible patients reported by Igarashi et al. (15, 16). These reports suggested that EVP could be administered to selected patients undergoing hemodialysis or those with severe renal dysfunction or poor PS; however, reproducibility could not be established because the evidence was limited to case reports. The present consecutive cohort provides additional descriptive real-world information regarding treatment courses and outcomes in this population.

The clinical course of platinum-ineligible patients in our cohort was heterogeneous. Some patients discontinued EVP early because of progressive disease or AEs, whereas others experienced objective responses, prolonged treatment exposure, or disease control after treatment interruption. These findings suggest that selected platinum-ineligible patients may derive clinical benefit from first-line EVP, but they should not be interpreted as evidence of equivalence between platinum-eligible and platinum-ineligible patients. Rather, the results support individualized treatment selection based on expected treatment tolerance, frailty, organ function, disease burden, and the feasibility of proactive toxicity management.

In exploratory univariate analyses, elevated C-reactive protein level, liver metastases, lung metastases, lower hemoglobin level, and ECOG PS ≥3 were associated with survival outcomes. These factors should be interpreted as prognostic markers reflecting tumor burden, systemic inflammation, anemia, and overall vulnerability, rather than as predictive markers indicating lack of benefit from EVP. Given the small number of patients and events, these findings should not be used to exclude patients from EVP. Instead, they may help identify patients who require closer monitoring, early supportive care, and timely treatment modification during EVP.

Safety remains a key concern in frail patients. The most common treatment-related AEs in this study, including skin toxicity, dysgeusia, and fatigue, were consistent with the known safety profile of EVP. In the platinum-ineligible subgroup, grade ≥3 treatment-related AEs were infrequent, and no grade ≥3 hyperglycemia was observed. However, given the small number of platinum-ineligible patients, no definitive conclusions can be drawn regarding comparative safety. Importantly, Furubayashi et al. demonstrated in patients receiving EV monotherapy that reductions in the relative dose intensity of EV did not significantly compromise treatment efficacy, suggesting that appropriate dose modification for AE management may preserve both treatment continuity and antitumor activity (17). Although these findings were derived from EV monotherapy rather than EVP, they support a strategy of proactive toxicity management in clinically vulnerable patients. Although uncommon, rare but clinically important toxicities have also been reported during EVP therapy. Bamba et al. described a case of severe esophageal ulceration associated with EVP, highlighting the importance of careful surveillance for atypical gastrointestinal AEs in addition to well-recognized toxicities such as skin toxicity, peripheral neuropathy, pneumonitis, and hyperglycemia (18). Therefore, careful patient selection, proactive monitoring, early treatment interruption when appropriate, dose modification, and multidisciplinary supportive care remain essential to maximize the clinical benefit of EVP, particularly in platinum-ineligible patients.

Limitations. First, it was retrospective and conducted at a single institution. Second, the sample size was small, particularly in the platinum-ineligible subgroup. Third, follow-up was relatively short, and survival estimates in the platinum-ineligible subgroup were immature. Fourth, radiologic response was not evaluable in some patients. Fifth, platinum eligibility was determined retrospectively using criteria adapted from prior real-world studies, and comorbidity assessment depended on medical record documentation. Finally, multivariable analysis was not performed because of the limited number of events. These findings should therefore be considered descriptive and hypothesis-generating, and validation in larger multicenter cohorts is warranted.

First-line EVP demonstrated encouraging antitumor activity and acceptable tolerability in selected platinum-ineligible patients with locally advanced or metastatic UC. Individual treatment trajectories were heterogeneous, with early discontinuation in some patients and prolonged treatment exposure or disease control in others. Because the platinum-ineligible subgroup was small, these findings should be interpreted as descriptive and hypothesis-generating rather than as definitive evidence of efficacy or safety. Careful assessment of frailty, organ function, tumor burden, expected treatment tolerance, and the feasibility of toxicity management remains essential when considering EVP for platinum-ineligible patients.

The Authors declare that they have no conflicts of interest in relation to this work.

Go Kaneko contributed to the study conception and design, data collection, data analysis, interpretation of the results, and manuscript drafting. Daisuke Igarashi contributed to data collection and critical revision of the manuscript. Suguru Shirotake contributed to supervision, interpretation of the results, and critical revision of the manuscript. All Authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

The Authors thank Medical English Service for English language editing.

During the preparation of this manuscript, a large language model (ChatGPT) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.