Abstract
Background/Aim: Enfortumab vedotin (EV) has been approved for the treatment of advanced urothelial carcinoma (UC) following platinum-based chemotherapy and immune checkpoint inhibitors (ICIs). However, there is no established treatment for patients whose disease progresses while on EV, and the clinical outcomes post-EV treatment are unclear.
Patients and Methods: From December 2021 to January 2025, 33 patients with advanced UC received EV monotherapy. After excluding those who discontinued EV due to adverse events or continued treatment without progression, 18 patients were retrospectively analyzed.
Results: The median follow-up was 4.1 months, and 16 patients (88.9%) died at the last follow-up. Ten patients received post-EV treatment (five received chemotherapy and five received ICIs), and eight opted for best supportive care (BSC). The overall survival (OS) was not significantly different between the post-EV and BSC groups (4.6 vs. 3.7 months, p=0.425). No significant differences in the progression-free survival (2.5 vs. 3.2 months, p=0.945) or OS (2.6 vs. 5.1 months, p=0.832) were observed between chemotherapy and ICI treatment in the post-EV treatment group. Patients with lymph node-only metastases had significantly longer OS than those with other metastases (13.5 vs. 3.3 months, p=0.039) in the post-EV treatment group.
Conclusion: Post-EV treatment did not significantly improve the survival compared with BSC in patients with advanced UC. However, patients with lymph node-only metastases may show better outcomes than others. Further research is required to identify effective treatment strategies for this population.
Introduction
The treatment landscape for advanced urothelial carcinoma (UC) has undergone a significant transformation in recent years. The latest National Comprehensive Cancer Network guidelines (1) recommend the combination of enfortumab vedotin (EV) and pembrolizumab as a preferred (category 1) regimen based on the results of the EV-302 trial, regardless of cisplatin eligibility (2), and this combination has been approved in Japan as first-line treatment since September 2024. In addition, for cisplatin eligibility, combination therapy with nivolumab plus gemcitabine–cisplatin followed by nivolumab maintenance therapy is recommended as the other preferred (category 1) regimen based on the results of the CheckMate 901 trial (3) and this regimen has been approved in Japan as first-line treatment since December 2024. These novel first-line regimens have demonstrated outcomes superior to conventional chemotherapy with gemcitabine and either cisplatin or carboplatin, which has long been the standard of care. However, despite the advent of combination therapy with immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) or platinum-based chemotherapy as a first-line therapy, advanced UC remains aggressive and generally incurable, requiring second-line or later treatment.
In contrast, gemcitabine and cisplatin (in cisplatin-eligible) or carboplatin (in cisplatin-ineligible) followed by avelumab maintenance, which was previously the preferred regimen, is still listed under “other recommended regimens (category 1)” based on the results of the JAVELIN Bladder 100 trial (4). After progression to avelumab maintenance, EV monotherapy is recommended based on the results of the EV-301 trial, which revealed that EV significantly prolonged the survival compared with standard chemotherapy in patients who had previously received platinum-based therapy and programmed death (PD) 1 and PD-ligand (L)-1 inhibitors (5).
However, no clinical trials have evaluated the treatment strategies for patients who progress on EV, leaving a critical gap in therapeutic guidance. In the absence of established post-EV treatment recommendations, many clinicians hesitate to propose additional therapy, often defaulting to best supportive care (BSC). Nonetheless, a subset of patients remains motivated to pursue further treatment despite uncertain efficacy.
The present study retrospectively evaluated the clinical outcomes of post-EV treatment compared with BSC in patients with advanced UC who have progressed on platinum-based chemotherapy, ICIs, and EV.
Patients and Methods
Patients. Between December 2021 and January 2025, 33 consecutive patients with advanced UC, either metastatic or locally advanced, received EV monotherapy following radiologic progression with platinum-based chemotherapy and ICIs. Patients were excluded if they discontinued EV owing to adverse events (n=7), continued EV without progression (n=4), or had identical dates for EV progression assessment and death (n=4). Consequently, a total of 18 patients were included in the final analysis.
Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (6). Clinical and follow-up data were obtained from the medical records. Informed consent was obtained via an opt-out process owing to the retrospective nature of the study. This study was approved by the Institutional Review Board of the National Hospital Organization Kyushu Cancer Center (Approval No. 2014-99).
Statistical analyses. All statistical analyses were conducted using EZR ver. 1.40 (Easy R, Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (7). Continuous variables were compared using the Mann–Whitney U-test, whereas categorical variables were analyzed using Fisher’s exact test. The progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The PFS was defined as the time from EV progression to radiographic progression after EV treatment, or death, whichever occurred first. The OS was defined as the time from EV progression to death. Patients without any event were censored at the last follow-up visit. The log-rank test was used to compare the PFS and OS between the treatment groups.
Univariate Cox proportional hazard regression models were used to assess the association between clinical variables and the OS. Statistical significance was set at p<0.05.
Results
Patient characteristics. Eighteen patients with radiological progression on EV monotherapy were included in the final analysis after excluding those who discontinued or changed treatment due to adverse events. Of these, 10 patients received post-EV treatment, while 8 opted for BSC. The median follow-up was 4.1 [interquartile range (IQR)=2.3-7.1] months, and at the last follow-up, 16 patients (88.9%) had died.
The median patient age was 72 (IQR=68-78) years old, and 12 patients (66.7%) were male (Table I). Nine patients (50.0%) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2. Histological analysis confirmed pure UC in 12 (66.7%) patients. Prior to EV, 14 patients (77.8%) received two treatment regimens. The objective response and disease control rates (DCRs) for EV were 33.3% (n=6) and 61.1% (n=11), respectively. At the initiation of post-EV treatment, 13 patients (72.2%) had visceral metastases, while only two patients (11.1%) had lymph node-only metastases. Among the 10 patients who received post-EV treatment, five underwent chemotherapy (three received gemcitabine/carboplatin, and two received paclitaxel/carboplatin), and all five also received the ICI pembrolizumab. Only the DCR for EV was significantly different between the post-EV treatment and BSC groups (p= 0.007). In addition, only the DCR of EV was significantly different between the yes and no treatment groups (p=0.007).
Patient characteristics.
Clinical outcome of post-EV treatment. Among patients receiving post-EV treatment, progressive disease was observed in nine patients (90%), while stable disease was confirmed in only one patient (10%). In the overall cohort, the median OS was 4.6 months [95% confidence interval (CI)=2.2-7.4]. No significant difference in the OS was observed between the post-EV treatment and BSC groups (4.6 vs. 3.7 months, p=0.425) (Figure 1).
The overall survival in the entire cohort based on whether post-enfortumab vedotin (EV) treatment was received.
Among patients who received post-EV treatment, the log-rank test showed no significant difference in PFS between chemotherapy and immune checkpoint inhibitors (2.5 vs. 3.2 months, p=0.945) (Figure 2). Similarly, the OS did not differ significantly between chemotherapy and immune checkpoint inhibitor treatment (2.6 vs. 5.1 months, p=0.832) (Figure 3). When stratified by metastasis site, patients with lymph node-only metastases had a significantly longer OS than those with other metastases (13.5 vs. 3.3 months, p=0.039) (Figure 4).
The progression-free survival in patients who received post-enfortumab vedotin (EV) treatment, according to chemotherapy or immune checkpoint inhibitor.
The overall survival in patients who received post-enfortumab vedotin (EV) treatment, according to chemotherapy or immune checkpoint inhibitor.
The overall survival in patients who received post-enfortumab vedotin (EV), based on lymph node-only metastases or metastases including other sites.
Univariate analyses for the OS in patients receiving treatment. Univariate Cox regression analyses showed that none of the clinical variables, including the age, ECOG PS, sex, histology, visceral metastases, or post-EV treatment, were significantly associated with the prognosis (p=0.730, 0.678, 0.192, 0.060, 0.234, and 0.908, respectively) (Table II).
Univariate analyses for the overall survival (OS) in patients receiving treatment.
Discussion
This retrospective study evaluated the post-EV treatment outcomes in patients with advanced UC. The results showed no significant survival benefit in the post-EV treatment group compared to that in the BSC group. In addition, among patients receiving post-EV treatment, there were no significant differences in the PFS or OS between the chemotherapy and ICI groups. However, patients with lymph node-only metastases had a significantly longer OS than those with other metastases.
UC remains a highly challenging malignancy with poor prognosis, particularly in the advanced or metastatic stages (8-14). The emergence of novel first-line combination therapies, such as ICIs with ADCs or chemotherapy, has expanded the scope of treatment (2, 3). However, UC remains a refractory disease with significant unmet clinical needs. Further research on post-progression treatment strategies is crucial to improve therapeutic efficacy and patient outcomes.
The EV-301 trial demonstrated that EV monotherapy provided superior efficacy over chemotherapy in patients previously treated with platinum-based chemotherapy and PD-1 or PD-L1 inhibitors (5). However, owing to the absence of robust clinical trial data and limited real-world evidence on post-EV treatment, whether or not these therapies offer meaningful survival benefits or symptom relief remains unclear. Consequently, clinicians face significant uncertainty in determining the optimal management strategy for patients with EV progression. While the EV-301 trial has recently reported 24-month follow-up data, it offers insights into long-term outcomes but does not specifically address the efficacy of post-EV treatments (15). Consequently, physicians often rely on limited real-world post-treatment data or empirical decision-making when determining the next course of action.
A retrospective study of 63 patients who discontinued EV reported poor outcomes, with a median OS of only 32 weeks. In this cohort, only 51% of the patients received therapy after EV discontinuation. Among those who underwent post-EV therapy, the objective response rate was only 9.4%, whereas 59.4% experienced progressive disease (unknown in 18.8%). However, patients who received post-EV therapy had a significantly longer OS than those who did not (43.1 weeks vs. 16.9 weeks, p=0.015) (16). The present study confirmed the poor outcomes observed, with a median OS of 4.6 months across the overall cohort, and 90% of the patients receiving post-EV treatment experienced disease progression. In addition, no significant differences in the PFS or OS were found between patients who received post-EV treatment and those who opted for BSC. The lack of survival difference between the treated and untreated groups may be attributed to the fact that this study only included patients who discontinued EV due to disease progression rather than adverse events. This suggests that the patients included in this study were already at an advanced stage of the disease, potentially limiting the efficacy of subsequent treatments.
In Japan, insurance regulations currently restrict patients to treatment with the same mechanism of action as their previous therapy, such as chemotherapy or ICIs. Physicians typically select a post-EV treatment regimen based on the patient’s response to therapies administered before EV. Erdafitinib is an oral, selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor (17). It has been reported that erdafitinib therapy significantly prolongs the OS compared with chemotherapy in patients with metastatic UC and FGFR alterations who have previously received anti–PD-1 or anti–PD-L1 treatment (18). In addition, studies have examined the impact of therapy sequencing in patients with advanced UC harboring FGFR2/3 alterations who received both erdafitinib and EV. No significant difference in the OS was observed between the erdafitinib-then-EV and EV-then-erdafitinib groups (19), suggesting that erdafitinib may remain a viable treatment option even after disease progression in patients with FGFR2/3 alterations.
The outcomes of patients receiving post-EV therapy were poor. However, a longer duration of prior EV therapy was reported to be associated with a higher likelihood of receiving post-EV therapy (p=0.0437), as well as an improved OS in both the treated (p=0.045) and untreated (p= 0.012) groups (16). These results suggest that the survival benefit may not necessarily stem from post-EV treatment itself but rather from the intrinsic nature of the disease. The present study revealed a significant difference in the OS between patients with lymph node-only involvement and those with other metastatic sites, who were treated with post-EV therapy. This significant difference in the OS based on lymph node involvement suggests that metastatic disease distribution also plays a key role in the prognosis. In fact, it has been reported that patients with a low tumor burden (e.g., lymph node-only disease) and non-visceral metastases have been associated with a more favorable prognosis than others (9, 20, 21). Taken together, these findings suggest that a subgroup of patients with an intrinsically less aggressive disease course may have a longer OS than others, regardless of post-EV therapy administration.
Even if physicians believe that BSC is the most appropriate option, based on the results of this study, they cannot refuse treatment if the patient requests it. Differences in the perceptions of a “good death” among patients with cancer, the general population, oncologists, and oncology nurses in Japan have been reported (22). The findings revealed significant discrepancies in the perceived importance of “fighting against cancer” between patients and medical professionals. The desire to “fight cancer” differed significantly between patients and oncologists (p=0.001) and between patients and oncology nurses (p=0.001). Patients who prioritized “maintaining hope and pleasure” (p=0.0001), “unawareness of death” (p= 0.0001), and a “good relationship with family” (p= 0.004) were more likely to favor “fighting against cancer.” In contrast, patients who placed greater emphasis on “physical and psychological comfort” were less likely to support “fighting against cancer” (p=0.004). These results highlight the need for healthcare providers to recognize the diverse values of end-of-life care. Understanding patients’ perspectives and incorporating their values into shared decision-making may enhance patient satisfaction and improve the overall quality of life, even when the prognosis is limited.
Our study has several limitations, including the small sample size, retrospective design, lack of randomization, and potential treatment selection bias by physicians, particularly in decisions regarding whether to initiate treatment. In addition, variability among physicians in therapy selection, imaging intervals, and follow-up duration is likely. Therefore, external validation using larger datasets is necessary.
Conclusion
Post-EV treatment does not significantly improve the survival compared with BSC in patients with advanced UC. However, patients with lymph node-only metastases may experience better outcomes than others, even in the post-EV treatment group. Further research is needed to identify effective treatment strategies for this patient population.
Acknowledgements
The Authors thank Japan Medical Communication (https://www.japan-mc.co.jp/) for editing the English language of this manuscript.
Footnotes
Authors’ Contributions
Study concept and design: N.F., M.N. and T.N.; acquisition of data: N.F., M.M., A.K., Y.F., M.N. and N.T.; statistical analysis: N.F., and T.N.; analysis and interpretation of data: all Authors; drafting of the original manuscript: N.F., M.N. and T.N.; critical revision of the manuscript for important intellectual content: all Authors; supervision: M.N. and T.N. All Authors have read and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest related to this study.
Funding
No funding was received for this study.
- Received March 26, 2025.
- Revision received April 7, 2025.
- Accepted April 8, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
