Abstract
Background
The treatment strategy for urothelial carcinoma has advanced with the development of enfortumab vedotin (EV); however, a comparative analysis of its therapeutic efficacy between upper urinary tract urothelial carcinoma (UTUC) and bladder cancer (BCa) has yet to be established. We aimed to compare the effects of EV after pembrolizumab treatment between the patients with UTUC and BCa.
Methods
We included the patients with advanced UC patients who received EV after pembrolizumab in this retrospective study. We investigated the impact of various clinical variables including age, primary site of disease (UTUC vs. BCa), Liver metastasis, lung metastasis, prior number of regimens before EV treatment, and ECOG PS, which influenced on prognosis and efficacy of EV treatment.
Results
A total of 63 male and 23 female patients were included in our study. The number of UTUC and BCa patients were 33 and 53, respectively. The UTUC cohort had a significantly older patient population and a greater incidence of lung metastases compared to the BCa group. The prognosis of UTUC patients were not significantly different from BCa patients. However, UTUC was determined as significant factor to predict better overall response rate than BCa in multiple logistic regression analysis.
Conclusions
UTUC patients showed significantly better response to EV treatment than BCa patients.
Keywords: Upper urinary tract urothelial carcinoma (UTUC), bladder cancer (BCa), enfortumab vedotin (EV)
Highlight box.
Key findings
• We investigated the effects of enfortumab vedotin (EV) treatment on metastatic or locally advanced urothelial carcinoma patients. Although much higher number of lung metastasis cohorts were observed in upper urinary tract urothelial carcinoma (UTUC) than in bladder cancer (BCa), UTUC patients showed better overall response to EV treatment than BCa patients in this study.
What is known and what is new?
• The prognosis of UTUC is known as poorer than that of BCa patients.
• The comparison of efficacy of EV treatment between UTUC and BCa patients has not been reported.
• The efficacy of EV treatment is more prominent in UTUC patients with much higher ratio of lung metastasis cohorts than in BCa patients.
What is the implication, and what should change now?
• Future prospective studies are necessary to elucidate the different effects of EV treatment between UTUC and BCa patients.
• Molecular difference between UTUC and BCa might involve the efficacy of EV treatment, and which should be clarified in future studies.
Introduction
Upper urinary tract urothelial carcinoma (UTUC) shares similar histology type with bladder cancer (BCa). However, the molecular profiles of UTUC and BCa are different, and UTUC is known as poor prognosis disease (1,2). Recently, immune checkpoint inhibitors (ICIs) and enfortumab vedotin (EV), an antibody-drug conjugate directed against nectin-4, significantly improved the prognosis of UC patients including UTUC (3,4). There were several clinical studies which examined significant factors influencing the effects of EV treatment in metastatic or locally advanced (m/la) UC patients (5-8). Currently, research investigating molecular profiles of UC is of growing interest in the targeted therapy era (1). UC is divided into basal and luminal subtypes based on gene expression analysis. UTUC is predominantly categorized into luminal subtype according to several researches (9,10). It was reported that UC with nectin-4 immunopositivity was significantly higher in luminal UC patients (11,12). Furthermore, it was previously reported that UTUC patients had abundant nectin-4 protein expression (13,14). Thus, UTUC patients could derive treatment-related benefit from EV therapy. The aim of this study was to compare the efficacy of EV treatment between UTUC and BCa patients. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-254/rc).
Methods
This retrospective study was carried out across multiple institutions, including Kindai University Faculty of Medicine (Osaka, Japan), Jikei University School of Medicine (Tokyo, Japan), Osaka Medical and Pharmaceutical University (Osaka, Japan), Fujita Health University School of Medicine (Aichi, Japan), and Tokyo Medical University (Tokyo, Japan) from January 2018 to July 2023. The study was carried out in accordance with the Declaration of Helsinki and its subsequent amendments. Approval was obtained from the institutional review board of Kindai University Hospital (approval No. R02-155), and written informed consent was waived due to the retrospective study design. Furthermore, this study is a multicenter collaborative research project that was centrally reviewed and approved by the Ethics Committee of Kindai University Hospital. All participating hospitals/institutions were informed and agreed the study.
Inclusion criteria were the patients with m/la UC, and they were treated with EV after the progression from chemotherapy and pembrolizumab therapy.
Radiological evaluations were generally initiated using computed tomography (CT) scans both before and after every 3 to 6 cycles of EV treatment. Additional imaging was performed at the discretion of the attending physicians when clinically indicated. Tumor response was assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, following the methodology described in prior literature (15). The best response at each metastatic site was classified into four categories: (I) complete response (CR), defined as total resolution of lesions or a reduction of all lymph node metastases to less than 10 mm in short-axis diameter; (II) partial response (PR), indicating a decrease in tumor size of more than 30%; (III) stable disease (SD), in which the observed changes did not meet the thresholds for CR, PR, or progressive disease (PD); and (IV) PD, defined as an increase in tumor size exceeding 20%. Overall response rate (ORR) is measured from the proportion of patients who are met for CR or PR. We assessed performance status (PS) using Eastern Cooperative Oncology Group (ECOG) PS (16). EV was delivered intravenously at a dose of 1.25 mg/kg over a 30-minute infusion on days 1, 8, and 15 of each 28-day treatment cycle.
Overall survival (OS) and progression-free survival (PFS) between UTUC and BCa patients were evaluated and compared using Kaplan-Meier survival curves and the log-rank test. To determine independent predictors associated with achieving an ORR, a multivariable analysis was performed.
Statistics
Comparisons between variables in the two groups were performed using the chi-square test, Fisher’s exact test, or the Mann-Whitney U test, as appropriate. In univariate and multivariate logistic regression analyses, we incorporated the variables including age (<75 vs. ≥75 years), primary site of disease (UTUC vs. BCa), Liver metastasis (yes or no), lung metastasis (yes or no), prior number of regimens before EV treatment (1 or 2 vs. ≥3), and ECOG PS (0 vs. ≥1). All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria), as previously described (17). A P<0.05 was considered indicative of statistical significance.
Results
A total of 86 patients received the EV therapy after pembrolizumab treatment. A total of 81 patients were treated with the standard EV dose, while one patient with BCa and four with UTUC initiated therapy at a reduced dose of 1.00 mg/kg body weight. The group with UTUC included significantly older patients (P<0.001) and higher proportion of patients with lung metastasis (P=0.004), and received fewer number of systemic therapies prior to EV treatment (P=0.03) than the group with BCa (Table 1). The summary of best overall responses to EV therapy is presented in Table 2. ORR was significantly worse in BCa compared with UTUC patients (P=0.047). However, there was no significant difference between BCa and UTUC patients in the duration of response, time from ORR to PD or last assessment (Table 2). There has been a trend toward BCa patients experiencing PD compared with UTUC patients but without statistical significance (Table 2). Univariate logistic regression analysis showed that UTUC [odds ratio, 2.54; 95% confidence interval (CI): 1.04–6.20; P=0.041] and ECOG PS (odds ratio, 0.24; 95% CI: 0.09–0.58; P=0.001) were significant predictors of ORR. When we proceed to multivariate logistic regression analysis, primary site of disease (UTUC vs. BCa) and ECOG PS (0 vs. ≥1) were incorporated in the analysis. Multivariate logistic regression analysis showed that UTUC (odds ratio, 3.08; 95% CI: 1.16–8.21; P=0.02) and ECOG PS (odds ratio, 0.21; 95% CI: 0.08–0.54; P=0.001) were significant predictive factors for ORR. The prior number of therapies did not significantly affect ORR (Table 3). Furthermore, we divided the patients into two groups, with or without ORR. As a result of analysis, the patients with ORR had significantly higher number of lymph node metastasis and UTUC patients, and a trend of higher number of lung metastasis than the patients without ORR. Moreover, the patients without ORR were worse ECOG PS than BCa patients (Table 4). On the other hand, PFS did not differ statistically between UTUC (median, 5.83 months) and BCa patients (median, 4.90 months) (Log-rank test, P=0.21) (Figure 1). OS was not significantly different between UTUC (median, 9.67 months) and BCa patients (median, 10.3 months) (Log-rank test, P=0.66) (Figure 1).
Table 1. Patient’s characteristics.
| Characteristics | UTUC (n=33) | BCa (n=53) | P value |
|---|---|---|---|
| Age (years) | 78.0 [59–90] | 73.0 [43–90] | <0.001* |
| Sex | 0.21 | ||
| Male | 27 (81.8) | 36 (67.9) | |
| Female | 6 (18.2) | 17 (32.1) | |
| ECOG PS | 0.14 | ||
| 0 | 14 (42.4) | 24 (45.3) | |
| 1 | 15 (45.5) | 12 (22.6) | |
| 2 | 1 (3.0) | 8 (15.1) | |
| 3 | 2 (6.1) | 6 (11.3) | |
| 4 | 1 (3.0) | 3 (5.7) | |
| Histology | >0.99 | ||
| Urothelial carcinoma | 29 (87.9) | 47 (88.7) | |
| Squamous cell carcinoma | 1 (3.0) | 1 (1.9) | |
| Adenocarcinoma | 3 (9.1) | 3 (5.7) | |
| NA | 2 (6.1) | 2 (3.8) | |
| Prior surgery or radiation | 0.16 | ||
| Surgery | 23 (69.7) | 29 (54.7) | |
| Radiation | 1 (3.0) | 5 (9.4) | |
| Surgery + radiation | 1 (3.0) | 2 (3.8) | |
| None | 8 (24.2) | 17 (32.1) | |
| Metastatic site | |||
| Bone metastasis | 8 (24.2) | 16 (30.2) | 0.63 |
| Lung metastasis | 21 (63.6) | 24 (45.3) | 0.004* |
| Liver metastasis | 9 (27.3) | 9 (17.0) | 0.28 |
| Lymph node metastasis | 15 (45.5) | 24 (45.3) | >0.99 |
| Duration of pembrolizumab (months) | 4.54 [0.7–30.4] | 4.43 [0.7–28.3] | 0.51 |
| Objective response of pembrolizumab | 0.33 | ||
| CR | 0 (0) | 4 (7.5) | |
| PR | 5 (15.2) | 8 (15.1) | |
| SD | 5 (15.2) | 12 (22.7) | |
| PD | 23 (69.7) | 29 (54.7) | |
| Prior number of regimen (chemotherapy or pembrolizumab) | 0.03* | ||
| 1 | 0 (0) | 2 (3.8) | |
| 2 | 22 (66.7) | 21 (39.6) | |
| 3 or more | 11 (33.3) | 30 (56.6) | |
Data are presented as median [range] or number (percentage), as appropriate. *, P<0.05 is considered as significant. BCa, bladder cancer; CR, complete response; ECOG, Eastern Cooperative Oncology Group; NA, not applicable; ORR, overall response rate; PD, progression disease; PR, partial response; PS, performance status; SD, stable disease; UTUC, upper urinary tract urothelial carcinoma.
Table 2. Best overall response rate during EV treatment.
| Response category | UTUC (n=33) | BCa (n=53) | P value |
|---|---|---|---|
| CR | 0 (0) | 1 (0.02) | >0.99 |
| PR | 20 (60.6) | 19 (35.8) | 0.03* |
| ORR (CR + PR) | 20 (60.6) | 20 (37.7) | 0.047* |
| SD | 7 (21.2) | 13 (24.5) | 0.48 |
| PD | 6 (18.2) | 20 (37.7) | 0.09 |
| Duration of response (time from ORR to PD or last assessment) | 4.2 (0.1–19.7) | 3.3 (0.3–57.4) | 0.69 |
Data are presented as median (range) or number (percentage), as appropriate. *, P<0.05 is considered as significant. BCa, bladder cancer; CR, complete response; EV, enfortumab vedotin; ORR, overall response rate; PD, progression disease; PR, partial response; SD, stable disease; UTUC, upper urinary tract urothelial carcinoma.
Table 3. Multiple logistic regression analysis to predict ORR.
| Variable | Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | P | Odds ratio | 95% CI | P | ||
| Age (<75, ≥75 years) | 1.53 | 0.65–3.62 | 0.34 | ||||
| UTUC or BCa (yes or no) | 2.54 | 1.04–6.20 | 0.041* | 3.29 | 1.19–9.07 | 0.02* | |
| Liver metastasis (yes or no) | 1.58 | 0.56–4.51 | 0.38 | ||||
| Lung metastasis (yes or no) | 2.17 | 0.91–5.15 | 0.08 | ||||
| Lymph node metastasis (yes or no) | 3.10 | 1.28–7.50 | 0.01 | 2.91 | 1.10–7.68 | 0.03* | |
| Prior number of regimen (1 or 2 vs. ≥3) | 0.82 | 0.35–1.91 | 0.64 | ||||
| ORR with pembrolizumab (yes or no) | 0.57 | 0.24–1.38 | 0.22 | ||||
| ECOG PS (0 vs. ≥1) | 0.24 | 0.09–0.58 | 0.001* | 0.23 | 0.08–0.61 | 0.003* | |
*, P<0.05 is considered as significant. BCa, bladder cancer; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; ORR, overall response rate; PS, performance status; UTUC, upper urinary tract urothelial carcinoma.
Table 4. The patient’s characteristics according to with or without ORR.
| Variable | ORR+ (n=40) | ORR− (n=46) | P value |
|---|---|---|---|
| Age (years) | 75.0 [55–90] | 74.0 [43–90] | 0.37 |
| Sex | 0.81 | ||
| Male | 30 (75.0) | 33 (71.7) | |
| Female | 10 (25.0) | 13 (28.3) | |
| ECOG PS | 0.006* | ||
| 0 | 25 (62.5) | 13 (28.3) | |
| 1 | 11 (27.5) | 16 (34.8) | |
| 2 | 3 (3.0) | 6 (13.0) | |
| 3 | 1 (7.5) | 7 (15.2) | |
| 4 | 0 (0) | 4 (8.7) | |
| Primary lesion | 0.04* | ||
| BCa | 20 (50.0) | 33 (71.7) | |
| UTUC | 20 (50.0) | 13 (28.3) | |
| Histology | 0.12 | ||
| Urothelial carcinoma | 36 (90.0) | 40 (86.9) | |
| Urachal carcinoma | 0 (0) | 3 (6.5) | |
| Squamous cell carcinoma | 0 (0) | 2 (1.9) | |
| Adenocarcinoma | 1 (2.5) | 0 (4.3) | |
| NA | 3 (7.5) | 1 (2.2) | |
| Prior surgery or radiation | >0.99 | ||
| Surgery | 24 (60.0) | 28 (60.9) | |
| Radiation | 3 (7.5) | 3 (6.5) | |
| Surgery + Radiation | 1 (2.5) | 2 (4.3) | |
| None | 12 (30.0) | 13 (28.3) | |
| Metastatic site | |||
| Bone metastasis | 8 (20.0) | 16 (34.8) | 0.63 |
| Lung metastasis | 25 (62.5) | 20 (43.5) | 0.08 |
| Liver metastasis | 10 (25.0) | 8 (17.4) | 0.28 |
| Lymph node metastasis | 24 (60.0) | 15 (32.6) | 0.01* |
| Duration of pembrolizumab (months) | 3.87 [0.7–30.4] | 4.78 [0.7–28.3] | 0.81 |
| Best ORR of pembrolizumab | 0.33 | ||
| CR | 2 (5) | 2 (4.3) | |
| PR | 6 (15) | 7 (15.2) | |
| SD | 5 (12.5) | 12 (26.1) | |
| PD | 27 (67.5) | 25 (54.3) | |
| Prior number of regimen (chemotherapy or pembrolizumab) | 0.49 | ||
| 1 | 0 (0) | 2 (4.3) | |
| 2 | 22 (55.0) | 21 (45.7) | |
| 3 or more | 18 (45.0) | 23 (50.0) | |
Data are presented as median [range] or number (percentage), as appropriate. *, P<0.05 is considered as significant. BCa, bladder cancer; ECOG, Eastern Cooperative Oncology Group; NA, not applicable; ORR, overall response rate PS, performance status; UTUC, upper urinary tract urothelial carcinoma.
Figure 1.
The log-rank test was performed to evaluate PFS (A) and OS (B) between patients with UTUC and BCa. A P value of <0.05 was considered significant. BCa, bladder cancer; OS, overall survival; PFS, progression free survival; UTUC, upper urinary tract urothelial carcinoma.
Discussion
This is the first study to demonstrate that UTUC was a significant predictor of better ORR during EV treatment than BCa although UTUC patients had higher proportions of lung metastasis and geriatrics than BCa patients in this study. It has been reported that nectin-4 expression decreases as metastasis spread (18). However, the effectiveness of EV on lung, lymph node, and liver metastasis is known as favorable compared with other organs like bone metastasis (19,20). Our study showed significantly higher proportions of lymph node metastasis and UTUC patients, and a trend of higher number of lung metastasis patients in the group with ORR than in the one without ORR. The newly obtained finding in our study was that EV therapy was more effective in achieving better ORR in UTUC patients than in BCa patients. On the other hand, a previous retrospective study investigating EV monotherapy showed worse ECOG PS can diminish the treatment effectiveness (21). Furthermore, cross resistance induced by prior chemotherapy was observed in UC cell lines (22). These factors, including ECOG PS and prior treatment lines, can influence ORR, however UTUC has been determined as a significant independent predictive factor of ORR in multivariate logistic regression analysis. In a real-world clinical study, prior pembrolizumab did not affect the effectiveness of EV monotherapy (21). In our study, objective response rate of prior therapy with pembrolizumab did not affect the response of EV therapy. However, whether prior pembrolizumab could induce cross resistance with EV therapy should be further investigated. UTUC and BCa patients had distinct molecular profiles (1), and the two diseases should be treated with a different treatment strategy in the era of targeted therapy.
Elucidation of the molecular profiles of UC patients contribute to the prediction of treatment outcomes. UC can be classified into basal and luminal subtypes (9). Basal UC subtype has abundant tumor infiltrating CD8+T cells, and programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) expression on immune and cancer cells, respectively (23). The previous meta-analysis suggested that PD-L1 expression was associated with improved ORR, OS, and PFS in m/la UC patients who received PD-L1 inhibitor (24). Furthermore, neoadjuvant pembrolizumab prolong the recurrence free survival of the patients with basal UC subtype and high expression of PD-L1 (25). On the other hand, UTUC has been predominantly categorized into luminal subtype, which has T-cell depletion in its immune environment (26). Tumor infiltrating CD8+T cells are the markers of ICIs effectiveness (27). Therefore, it is controversial whether ICIs exert antitumor effectiveness for UTUC with T-cell depleted immune environment. The expression rate of PD-L1 is not associated with nectin-4 protein level in m/la UC patients (12). If ICIs did not show favorable outcomes for UTUC patients, EV therapy could be a promising subsequent treatment.
Nectin-4 is widely expressed in UC except neuroendocrine-like and sarcomatoid UC. Among UC patients, nectin-4 expression is highly expressed in luminal UC subtypes (11,12). Furthermore, it was reported that UTUC patients had high immunopositivity of nectin-4 (13,14). According to these previous researches, the target of EV treatment is abundant in UTUC patients. It has been reported that the primary lesion of disease, UTUC or BCa, did not affect the effects of EV therapy (28,29). However, these reports included relatively small number of patients, and the results might not be decisive. On the other hand, there have not been such studies where researchers compared the expression level of nectin-4 between UTUC and BCa. Recently, PET/CT imaging of UC patients using nectin-4 targeting radiotracer has been reported (30). This imaging study could clarify whether expression level of nectin-4 is higher in UTUC or BCa in the future. Furthermore, this kind of less invasive imaging study could be helpful for precision medicine of EV therapy.
In our study, UTUC patients showed significantly better ORR than BCa patients. The previous study (31) showed that ORR of BCa patients treated with EV monotherapy was around 50% vs. 37.7% in our study. BCa patients were treated with much higher number of prior therapies than UTUC patients. Therefore, it’s possible BCa patients might experience worse ORR due to the reason. A clinical trial in China suggested that ORR of UTUC and BCa patients was 27.6% (8/29) and 63.6% (7/11), respectively (32). However, there was a concern in this Chinese study which included small number of patients and patient’s characteristics of each UTUC and BCa were unclear. Furthermore, long-term outcomes of EV301 trial showed that OS of UTUC and BCa was 13.57 and 12.88 months, respectively (statistical significance was unknown) (33). These studies were subgroup analysis, and the detailed information of each UTUC and BCa patients was lacking. On the other hand, in our study, PFS did not differ between the two groups although UTUC patients showed better ORR over BCa patients. There was no statistical difference between two groups in the time to PD after they experienced ORR. UTUC is known as a poor prognosis disease compared with BCa (34). We suggest that geriatric UTUC patients with metastasis should be cautiously observed even after they have achieved ORR. Whether EV therapy derive favorable outcomes for UTUC over BCa patients should be investigated in the future study.
This study has several limitations. First, this retrospective study included small number of subjects. Therefore, future large scale prospective research is warranted. Second, we could not conduct immunohistochemistry and gene expression analysis in this retrospective multi-center study. Future studies are warranted to investigate whether effects of EV treatment for UTUC patients are associated with molecular profiles such as luminal subtypes. Third, UTUC patients showed better ORR than BCa patients. However, there was no statistical difference in OS and PFS between UTUC and BCa patients. In the future, clinical trials with well-matched patient backgrounds will be required.
Conclusions
Although UTUC patients demonstrated an improved ORR compared to BCa patients, no significant improvements were observed in OS or PFS. Further investigation is warranted to compare the effects of EV treatment on UC patients with well-matched patient backgrounds and to analyze molecular characteristics, including nectin-4 expression, between patients with UTUC and BCa.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was carried out in accordance with the Declaration of Helsinki and its subsequent amendments. Approval was obtained from the institutional review board of Kindai University Hospital (approval No. R02-155), and written informed consent was waived due to the retrospective study design.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-254/rc
Funding: None.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-254/coif). K.F. serves as an unpaid editorial board member of Translational Andrology and Urology from October 2019 to September 2025. The other authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-254/dss
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