FormalPara Key Points

The results confirm the effectiveness of enfortumab vedotin in patients with metastatic urothelial carcinoma following frontline chemotherapy and subsequent maintenance treatment with avelumab who were not included in the pivotal clinical trials.

The results confirm the safety profile of enfortumab vedotin.

1 Introduction

Frontline platinum-based chemotherapy has been used to treat patients with locally advanced/metastatic urothelial carcinoma (la/mUC) for decades. Although the treatment scenario is evolving, the most commonly used first-line treatment regimens are currently the combination of gemcitabine with cisplatin or carboplatin and the combination of methotrexate, vinblastine, adriamycin with cisplatin (M-VAC) [1, 2]. Patients without disease progression on platinum-based chemotherapy are candidates for the switch maintenance with avelumab, an immune checkpoint inhibitor (ICI) targeting the programmed cell death protein-ligand-1 (PD-L1) [3]. In the second-line setting, following progression on platinum-based chemotherapy, three ICIs targeting the PD-1/PD-L1 pathway are available, though with geographical differences, including pembrolizumab, nivolumab, and atezolizumab [4,5,6]. Enfortumab vedotin (EV) is an antibody targeting nectin-4 linked to a microtubule disrupting agent monomethyl auristatin E (MMAE), which has been approved for the treatment of patients with la/mUC who previously received platinum-based chemotherapy followed by PD-1/PD-L1 inhibitors. EV exhibited efficacy in a phase II and phase III clinical trials, which demonstrated significant improvement of both progression-free survival (PFS) and overall survival (OS), with higher response rates as compared with single-agent chemotherapy [3, 7]. However, EV has been approved for patients refractory to previous platinum-based chemotherapy and ICIs [8], it should be noted that the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy [3, 7]. Recently, the combination of EV plus pembrolizumab has emerged with positive results compared with chemotherapy in a randomized phase III trial, EV-302 [9]. This combination regimen has recently become the preferred first-line treatment for la/mUC. While the combination of EV plus pembrolizumab is beginning to be available in real-world clinical practice, the majority of patients continue to receive platinum-based chemotherapy in the frontline setting, which is still the current standard of care for many patients in many countries. Therefore, the real-world experience with EV after ICI, especially after avelumab, is of great interest.

The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2EV study.

2 Patients and Methods

2.1 Study Design

We retrospectively analyzed clinical data from mUC patients enrolled in ARON-2EV (NCT05290038), an international multicenter observational study designed to collect data on EV in patients progressing after platinum-based chemotherapy and ICIs. The ARON-2EV involved 50 oncological centers from 15 countries (Table S1). Patients selected for the present analysis were treated with EV after frontline platinum-based chemotherapy and avelumab switch maintenance. The clinical data were collected between 1 January 2022 and 30 April 2024 and were extracted at each participating center from the patients’ medical reports. Patients with missing clinical or outcome data were excluded from the analysis. Patients previously treated with adjuvant immunotherapy were not included. EV was administered intravenously as a single agent in the standard approved schedule (1.25 mg/kg given on days 1, 8, and 15 of each 28-day cycle). The treatment was continued until disease progression, unacceptable toxicity, or patient refusal. Physical examination and laboratory tests and computed tomography (CT) scans were performed following standard local procedures.

The study protocol was approved on 28 September 2023 by the Ethical Committee of the coordinating center (Marche Region, Italy – no. 2022 39/7875) and by the Institutional Review Boards of participating centers. The study was conducted according to Good Clinical Practice (GCP) and International Ethical Guidelines for Biomedical Research, and the protocol has been designed with the ethical principles laid out in the Declaration of Helsinki on human experimentation.

2.2 Study Objectives

The primary objective was to assess the outcome of patients with mUC treated with EV following avelumab maintenance. OS was calculated from the initiation of EV therapy until death for any cause. PFS was defined as the time from the EV initiation until progression or death from any cause. The objective response [progressive disease (PD), stable disease (SD), partial response (PR), complete response (CR)] was evaluated using the RECIST version 1.1.; iRECIST were not used for evaluation of response to avelumab [10]. Duration of response (DoR) was defined as the time from first imaging to assess the achievement of CR or PR with EV until disease progression or death from any cause. ORR was calculated as the sum of CR+PR. For the analysis of EV toxicity, only selected grade ≥ 3 adverse events (AEs) were reported, including overall incidence, peripheral neuropathy, skin rash, diarrhea, and hyperglycemia. The grade of AEs was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) [11].

2.3 Statistics

The comparison of PFS and OS between the groups was performed using the Kaplan–Meier method and log-rank test. The median follow-up was calculated with the Kaplan–Meier method. Patients without progression or death at their last follow-up were censored. Hazard ratios (HRs) were estimated using Cox proportional hazards regression models, 95% confidence intervals (CIs) were calculated for medians and HRs. To identify prognostic factors for PFS and OS, univariate and multivariate Cox proportional hazard regression models were performed. The comparison between subgroups was performed with the Fisher exact test. p-values < 0.05 were considered statistically significant. Statistical analyses were conducted using MedCalc version 19.6.4 (MedCalc Software, Broekstraat 52, 9030 Mariakerke, Belgium).

3 Results

3.1 Study Population

A total of 182 patients with mUC treated with EV were studied from the ARON-2EV dataset (Fig. S1). The median follow-up time was 12.0 months (95% CI 5.9–21.6); 125 (69%) patients were dead at the time of analysis. The clinical characteristics of the patients are summarized in Table 1.

Table 1 Baseline clinical characteristics of patients
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3.2 Survival

The median OS in the overall study population was 12.7 months (95% CI 10.2–14.1, Fig. 1). No significant differences were found stratifying patients by sex (p = 0.759), age at EV initiation (p = 0.529), or body mass index (BMI) (p = 0.771), primary tumor localization (p = 0.245), histology (p = 0.120), response to avelumab maintenance therapy (p = 0.557), and metastatic sites. A statistically significant difference in OS was found according to ECOG PS 0 (median OS 14.7 months, 95% CI 13.4–20.1), 1 (11.3 months, 95% CI 9.2–14.1), and 2 (4.8 months, 95% CI 2.4–7.9, p < 0.001, Fig. 2). The OS data are summarized in Table 2. The median PFS for EV was 7.9 months (95% CI 6.4–9.9, Fig. 1), with 83 patients (46%) progressing on EV and 99 patients ongoing treatment (54%). The median PFS for avelumab maintenance therapy was 4.0 months (95% CI 3.5–26.1). The median PFS for patients who had reached > 4 months PFS on avelumab (group A) was 10.0 months (95% CI 6.7–11.3) versus 6.3 months (95% CI 5.7–17.7, p = 0.019) for those who had reached ≤ 4 months PFS on avelumab (group B) (Fig. 3).

Fig. 1
figure 1

Overall survival and progression-free survival for patients treated with enfortumab vedotin for metastatic urothelial carcinoma following avelumab maintenance therapy

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Fig. 2
figure 2

Overall survival for patients treated with enfortumab vedotin for metastatic urothelial carcinoma following avelumab maintenance therapy stratified by Eastern Cooperative Oncology Group Performance Status (ECOG-PS)

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Table 2 Subgroup data for overall survival (OS)
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Fig. 3
figure 3

Progression-free survival (PFS) for enfortumab vedotin according to the median PFS of previous avelumab maintenance therapy

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3.3 Univariate and Multivariate Survival Analyses

In the univariate Cox model, ECOG PS (2 versus 0–1) was the only factor significantly associated with OS (HR 4.45, 95% CI 2.77−7.17, p < 0.001), while ECOG PS (2 versus 0–1) and duration of avelumab therapy (> 4 versus ≤ 4 months) were significantly associated with PFS [HR 2.38 (95% CI 1.67−3.38), p < 0.001 and HR 0.59 (95% CI 0.38−0.92), p = 0.021, respectively]. Subsequently, both ECOG PS and duration of avelumab therapy remained significant predictors of PFS in the multivariate Cox regression analyses [2.46 (95% CI 1.71−3.52), p < 0.001 and HR 0.56 (95% CI 0.36−0.89), p = 0.014, respectively] (Table 3).

Table 3 Univariate and multivariate survival analyses
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3.4 Objective Response

We further analyzed the best objective response to EV, showing 5% CR, 34% PR, 40% SD, and 21% PD, with an ORR of 39%. The median OS was not reached (NR) (95% CI NR–NR) for patients who achieved CR, 15.6 months (95% CI 12.2–20.1) for those who achieved PR, 11.3 months (95% CI 8.9–14.7) for those with SD, and 4.4 months (95% CI 3.4–13.7) for those with PD (p < 0.001). Disease patterns for patients who achieved CR are available in Table S2. The DoR in the 70 patients who achieved CR/PR was 10.9 months (95% CI 8.1–11.4). Patients who achieved CR/PR with avelumab maintenance therapy showed 9% CR, 42% PR, 30% SD, and 19% PD with EV; those who achieved SD reported 2% CR, 30% PR, 46% SD, and 22% PD with EV; and those with PD showed 5% CR, 33% PR, 39% SD, and 23% PD (Fig. 4). The ORR were 51%, 32%, and 38%, respectively (p = 0.020). Similarly to PFS, we further investigated the objective response to EV obtained in group A versus group B. Group A showed 8% of CR, 32% of PR, 43% of SD, and 17% of PD, while in group B we observed 2% of CR, 35% of PR, 36% of SD, and 27% of PD (ORR 40% versus 37%, p = 0.771).

Fig. 4
figure 4

Objective response to enfortumab vedotin (EV) according to the objective response to avelumab maintenance therapy prior to EV. EV enfortumab vedotin, CR complete response, PR partial response, SD stable disease, PD progressive disease

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3.5 Safety

A total of 37 patients (30%) experienced grade ≥ 3 AEs. The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia. The incidence of grade ≥ 3 AEs was higher in the group A compared with group B (30% versus 13%, p = 0.006).

4 Discussion

Data from the present retrospective study including 182 patients with mUC treated with EV following avelumab maintenance therapy confirm the efficacy of EV and support its use in this patient population. We observed an ORR of 39%, with DoR of 10.9 months. The median PFS and OS were 7.9 and 12.7 months, respectively.

The treatment landscape for la/mUC beyond front-line platinum containing chemotherapy regimens has been rapidly expanding in the recent years. The efficacy and safety of EV have been demonstrated in clinical trials as well as in real-world retrospective studies, and three prospective clinical trials have been of pivotal importance. A phase I trial, EV-101 (NCT02091999), focused on patients with various nectin-4-expressing tumors, including 155 patients with mUC [12, 13]. EV demonstrated impressive ORR of 43% in heavily pretreated patients with mUC, suggesting its high effectiveness. The median OS was 12.3 months. EV-201 (NCT03219333), a phase II non-randomized two-cohort clinical trial, investigated EV in patients with mUC who had received prior platinum-based chemotherapy (cohort 1) or those who were platinum-ineligible (cohort 2) and subsequently ICI [7]. EV reached an ORR of 44.0% with a DoR of 7.6 months, and an ORR of 52% was shown in cisplatin-ineligible patients who had received ICI [14]. The positive results led to a subsequent phase III study, EV-301 (NCT03474107). This randomized phase III clinical trial enrolled 608 patients and compared EV with chemotherapy in patients refractory to platinum-based chemotherapy and following ICIs [3, 15]. The median PFS and OS were 5.55 and 12.88 months for patients receiving EV versus 3.71 and 8.97 months for those treated with chemotherapy (PFS: HR 0.62, p < 0.001; OS: HR 0.70, p = 0.00142). This study proved superiority of EV over standard chemotherapy, leading to its approval for this patient population [8]. Treatment-related grade ≥ 3 AEs occurred in 52.4% of patients in the EV arm. The most common grade ≥ 3 AEs were neutrophil count decrease (6.1%), anemia (2.7%), rash (7.4%), fatigue (6.8%), diarrhea (3.4%), and peripheral neuropathy (5.1%). AEs of special interest (any grade) included 47.3% rash, 48.0% peripheral neuropathy, and 6.8% hyperglycemia. Data from a real-world clinical practice have been reported in four retrospective studies. A large retrospective study on EV administration after ICI has been conducted by Kawahara et al. [16]. They analyzed 6007 patients with mUC treated with pembrolizumab; 563 among them subsequently received EV. The results demonstrated extended OS for patients treated with EV as compared with those treated with chemotherapy (HR 0.71, p = 0.013). Of note, this study did not include patients treated with avelumab maintenance prior to EV. The UNITE is a real-world registry-based study focused on patients with la/mUC who received EV. The initial analysis included 260 patients treated with EV and demonstrated an ORR of 52% and median PFS and OS of 6.8 and 14.4 months, respectively [17]. In terms of treatment prior to EV, the majority of patients (67%) had received two or more lines of systemic therapy, including 128 (49.2%) patients who had been previously treated with platinum-based chemotherapy and ICI. In the UNITE study, prior ICI therapy was not specified and the outcomes according to the previous systemic therapy were not assessed in the initial analysis. Outcomes of 49 patients who received EV after avelumab maintenance were recently reported and showed an ORR of 54% and median PFS and OS of 7.0 and 13.3 months, respectively [18]. Another retrospective study exploring the efficacy of EV has been conducted by Fukuokaya et al. [19]. This study including 103 patients reported an ORR of 50.5%, median PFS and OS were 6.0 and 14.5 months, respectively. Regarding the treatment prior to EV, 79.0% of patients had received pembrolizumab and only 21% had been treated with avelumab. The outcomes according to the type of ICI prior to EV were not reported in detail. A retrospective analysis aiming to compare the efficacy of EV according to the prior treatment with avelumab or pembrolizumab in a cohort of 100 patients with mUC has recently been reported by Hirasawa et al. [20]. The study observed an ORR of 66.6% in EV after avelumab versus 46.8% in EV after pembrolizumab groups, respectively (p = 0.14). The median PFS and OS for EV following avelumab versus pembrolizumab were 10.4 versus 5.2 months (p = 0.039) and NR versus 14.7 months (p = 0.17), respectively. Thus, the results suggested superior PFS for patients treated with EV after avelumab, while OS showed no significant difference between the two groups. The analysis of subsequent treatment after avelumab from an ambispective study, AVENANCE, has been reported by Barthelemy et al. Their results confirm the effectiveness of avelumab maintenance and showed encouraging OS in a cohort of 52 patients receiving EV following avelumab. Median OS from the initiation of avelumab was 31.3 months for the subsequent EV cohort, while the survival for EV separately was not shown [21].

Data on outcomes with EV in patients treated with frontline platinum-based chemotherapy followed by avelumab switch maintenance prior to EV are very limited due to the fact that those were not included in the prospective clinical trials, and the three retrospective studies to date included only small numbers of patients. Compared with the survival data from the EV-301 phase III trial, we observed slightly shorter PFS and similar OS, despite the different patient population with respect to the prior ICI treatment strategy [3, 15]. The results of Cox multivariate survival analyses in our study revealed inferior PFS for patients with ECOG PS 2 and those with duration of previous avelumab therapy ≤ 4 months, which is in line with data reported by Nizam et al. [18]. We found that patients who had achieved CR or PR with avelumab had significantly higher ORR compared with those with SD or PD with avelumab. However, such an effect was not seen for OS, suggesting that EV appears to have a survival benefit regardless of prior response to avelumab. Regarding toxicity, in comparison with EV 301 trial, we observed lower overall incidence of grade ≥ 3 AEs (30% versus 52.4%), while we found higher rate of grade ≥ 3 diarrhea (8% versus 3.4%), skin rash (9% versus 7.4%), and peripheral neuropathy (9% versus 5.1%) [3].

The role of predictive biomarkers in the frame of personalized oncology has been developing. The potential predictive role of several easily accessible biomarkers derived from peripheral blood has been of interest also in patients with mUC treated with EV. Uchimoto et al. have recently reported that C-reactive protein–albumin ratio predicts ORR to EV [22]. In our study, we focused strictly on basic clinical aspects of the treatment with EV following avelumab maintenance in patients with mUC. However, to find effective and easily accessible predictive and prognostic biomarkers for EV is an important issue in the current research.

Major limitations of the present study include retrospective design, lack of a central radiology review board, lack of detailed data on premature discontinuation of treatment, and relatively limited sample size. Furthermore, the evaluation of safety profile was limited due to the retrospective design and only selected grade ≥ 3 AEs were taken into account. Nevertheless, our study included the largest cohort of patients with mUC treated with platinum-based chemotherapy following avelumab maintenance prior to EV. In addition, our study included patients from various countries and represents a truly global patient dataset.

5 Conclusions

The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab.