Clinical Feasibility of Platinum-Based Chemotherapy Followed by Avelumab Maintenance after Enfortumab Vedotin plus Pembrolizumab in Metastatic Urothelial Carcinoma: A Case Series

Abstract

Introduction

The introduction of enfortumab vedotin plus pembrolizumab (EVP) has caused a paradigm shift in the first-line treatment strategies for metastatic urothelial carcinoma (mUC). However, no standard subsequent therapy has been established after EVP therapy, and the role of platinum-based chemotherapy (PBC) followed by avelumab maintenance therapy remains unclear.

Case Presentation

We report three cases of mUC treated with EVP followed by PBC and subsequent avelumab maintenance therapy. As the first-line treatment, EVP achieved disease control in all cases; however, disease progression or treatment discontinuation occurred. Subsequent PBC resulted in stable disease or partial response. Afterward, patients were transitioned to avelumab maintenance therapy, which resulted in further tumor regression or sustained disease control, even in patients with prior pembrolizumab exposure and those who discontinued EVP therapy due to adverse events.

Conclusion

PBC is often considered as a subsequent treatment after EVP therapy, except in patients with FGFR gene alterations. PBC followed by avelumab maintenance therapy may represent a feasible subsequent treatment option for selected patients with mUC who achieve disease control after EVP therapy.

Introduction

In recent years, the first-line treatment strategies for metastatic urothelial carcinoma (mUC) have undergone a major paradigm shift. In addition to conventional platinum-based chemotherapy (PBC), several new first-line treatment options have emerged, including enfortumab vedotin plus pembrolizumab (EVP) [1], gemcitabine-cisplatin (GC) plus nivolumab [2], and pembrolizumab monotherapy [3]. However, no standard subsequent therapy has been established after EVP or GC plus nivolumab. This report describes three cases of mUC in which PBC followed by avelumab maintenance therapy [4, 5] was administered after EVP therapy.

Case Presentation

Between October 2024 and August 2025, 28 patients with mUC received first-line EVP therapy at our institution. Among these, three patients subsequently proceeded to PBC followed by avelumab maintenance therapy after EVP discontinuation and are included in this report (Table 1). Tumor responses were retrospectively assessed based on routine computed tomography (CT) performed during clinical practice, according to RECIST version 1.1 principles when applicable, although formal centralized radiologic review was not conducted.

Table 1.

Baseline clinical characteristics, treatment course, and outcomes of three cases

Variable	Case 1	Case 2	Case 3
Age/sex	62/male	66/male	78/female
Primary site	Bladder	UTUC	Bladder
Prior perioperative therapy	Partial cystectomy + adjuvant ddMVAC	RNU + adjuvant GC	Neoadjuvant ddMVAC + RARC
Metastatic site	Lymph node	Lymph node	Liver
EVP cycles	7 cycles	10 cycles	1 cycle
Best response to EVP	SD	CR	PR
Reason for EVP discontinuation	PD	PD	AE (grade 3 erythema multiforme)
Platinum regimen	GC	ddMVAC	GC
Best response to platinum	PR	PR	PR
Duration of avelumab	6 months	3 months	6 months
Best response to avelumab	SD	PD	SD
Status at last follow-up	Avelumab ongoing	Erdafitinib start	Avelumab ongoing

UTUC, upper tract urothelial carcinoma; ddMVAC, dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin; GC, gemcitabine-cisplatin; RNU, radical nephroureterectomy; RARC, robot-assisted radical cystectomy; EVP, enfortumab vedotin plus pembrolizumab; CR, complete response; PR, partial response; SD, stable disease; PD, progression disease.

Case 1

A 62-year-old man underwent partial cystectomy for bladder cancer arising from a bladder diverticulum in October 2023. Postoperative pathological examination revealed UC (pT3, high-grade) with lymphovascular invasion. The patient received four cycles of adjuvant chemotherapy with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC). Twelve months postoperatively, CT revealed metastasis to the right internal iliac lymph node, and EVP therapy was initiated as first-line treatment (Fig. 1a), resulting in stable disease. However, disease progression was observed after the seventh cycle, and the patient developed hydronephrosis requiring percutaneous nephrostomy (Fig. 1b). GC was initiated after confirming the absence of actionable genetic alterations on comprehensive genomic profiling. Before the second cycle of GC, the patient developed pyelonephritis, resulting in a 2-week delay in treatment. Given that a partial response (PR) was observed on follow-up CT, the regimen was switched to avelumab maintenance therapy (Fig. 1c). Subsequently, further regression of the lymph node metastasis and improvement of hydronephrosis were observed. The nephrostomy tube was removed, and avelumab maintenance therapy has been continued for more than 6 months (Fig. 1d).

Fig. 1.

CT images showing right internal iliac lymph node metastasis. a Lymph node recurrence detected 12 months after partial cystectomy. b Disease progression with enlargement of the metastatic lymph node after seven cycles of EVP. c PR following one cycle of GC chemotherapy. d Further reduction of the lymph node metastasis during avelumab maintenance therapy.

Case 2

A 66-year-old man underwent laparoscopic radical nephroureterectomy for right ureteral cancer in October 2023. Postoperative pathological examination revealed high-risk disease (pT3, high-grade, lymphovascular invasion-positive), and the patient received four cycles of adjuvant chemotherapy with GC. Twelve months postoperatively, CT revealed multiple lymph node metastases, including the left supraclavicular and para-aortic lymph nodes, and EVP therapy was initiated (Fig. 2a). Complete response was achieved after three cycles of EVP therapy. However, disease progression was observed after 10 cycles, prompting initiation of subsequent therapy (Fig. 2b–d). Comprehensive genomic profiling revealed FGFR gene alterations; however, because erdafitinib was not yet approved in Japan at the time, ddMVAC chemotherapy was initiated at a reduced dose of 70%. After four cycles of ddMVAC, the patient achieved PR and was transitioned to avelumab maintenance therapy (Fig. 2e). However, disease progression occurred after six cycles, and erdafitinib was initiated thereafter [6] (Fig. 2f).

Fig. 2.

Coronal CT images of para-aortic lymph node metastases. a Baseline findings prior to initiation of enfortumab vedotin plus pembrolizumab (EVP) therapy. b Complete response after three cycles of EVP therapy. c Sustained complete response after six cycles of EVP therapy. d Disease progression with regrowth of lymph node metastases after ten cycles of EVP therapy. e PR after four cycles of ddMVAC chemotherapy. f Disease progression after six cycles of avelumab maintenance therapy.

Case 3

A 78-year-old woman underwent robot-assisted radical cystectomy with intracorporeal urinary diversion in September 2023 after receiving neoadjuvant ddMVAC chemotherapy. Postoperative pathological staging was ypT1N0M0; however, 13 months later, the patient developed recurrent disease with liver metastasis (Fig. 3a). EVP therapy was initiated but discontinued after one cycle due to grade 3 erythema multiforme (Fig. 3b). After resolution of this adverse event, GC was administered instead. The patient achieved PR and was transitioned to avelumab maintenance therapy, which has been continued for more than 6 months (Fig. 3c and d).

Fig. 3.

Contrast-enhanced CT images of liver metastasis. a Liver metastasis detected 13 months after robot-assisted radical cystectomy. b PR after one cycle of EVP therapy. c Further tumor reduction after three cycles of GC chemotherapy. d Sustained PR after more than 6 months of avelumab maintenance therapy.

Discussion

This case series highlights the potential clinical benefit of PBC followed by avelumab maintenance therapy after first-line EVP in patients with mUC. In the EV-302 trial, 128 patients (29%) received subsequent systemic therapy [1], most commonly PBC (25%), whereas no patients received avelumab maintenance therapy (0%). Notably, there are no clearly defined criteria or recommendations regarding the optimal number of cycles of PBC. Previous studies have shown that administering more than four cycles of PBC did not prolong survival and that a greater number of cycles were even associated with an increased risk of disease progression [7, 8]. Moreover, PBC alone cannot sufficiently maintain a durable long-term response [9]. Therefore, even after EVP therapy, avelumab maintenance therapy may be beneficial for patients who achieve at least stable disease or better with subsequent chemotherapy.

In cases in which pembrolizumab had been administered for a certain duration before disease progression (i.e., cases 1 and 2), the clinical benefit of subsequent avelumab maintenance therapy has not been fully established. The potential clinical activity of avelumab maintenance therapy even after prior exposure to pembrolizumab may be explained by fundamental pharmacological and immunological differences between programmed cell death protein 1 (PD-1) inhibitors and programmed death-ligand 1 (PD-L1) inhibitors. Pembrolizumab targets the PD-1 receptor expressed on T cells and blocks both PD-1-PD-L1 and PD-1-PD-L2 interactions, whereas avelumab selectively inhibits PD-L1 while preserving PD-L2-mediated signaling [10]. Because PD-L2 is expressed in several normal tissues, preservation of the PD-L2 pathway may contribute to more balanced immune modulation while maintaining antitumor activity. In addition, avelumab is an IgG1 monoclonal antibody capable of inducing antibody-dependent cellular cytotoxicity (ADCC) through engagement of Fcγ receptors on natural killer cells, whereas pembrolizumab is an IgG4 antibody lacking ADCC activity [11]. This unique property of avelumab may provide an additional antitumor mechanism beyond immune checkpoint blockade. Following cytotoxic chemotherapy or enfortumab vedotin, increased tumor antigen release and immune remodeling may further enhance the potential contribution of ADCC-mediated tumor cell elimination [12]. Therefore, switching from a PD-1 inhibitor to a PD-L1 inhibitor with distinct antibody characteristics may represent a biologically rational strategy rather than simple immune checkpoint inhibitor rechallenge. However, these pharmacological differences may only hypothetically contribute to clinical activity in some patients, and this possibility remains speculative and cannot be determined from the present case series.

Meanwhile, in cases wherein EVP therapy was discontinued due to adverse events (i.e., case 3), avelumab maintenance therapy may be particularly promising. Importantly, no grade ≥3 immune-related adverse events were observed during avelumab maintenance therapy in any of the present cases. In cases wherein FGFR gene alterations are identified (i.e., case 2), treatment with erdafitinib should not be overlooked, regardless of the treatment sequence. However, given the limited durability of responses to chemotherapy alone, avelumab maintenance therapy may still be clinically meaningful [9]. There are currently no validated biomarkers that can predict the benefit of avelumab maintenance therapy in this setting.

EVP has demonstrated favorable clinical outcomes regardless of cisplatin eligibility and is becoming an increasingly utilized first-line regimen for mUC. Thus, further studies are warranted to clarify the optimal subsequent treatment strategies. This report is limited by its small sample size and retrospective nature; therefore, these findings should be interpreted with caution. In addition, because only 3 of 28 patients treated with first-line EVP during the study period underwent this specific treatment sequence, the broader applicability of these observations remains limited. Furthermore, the marked clinical heterogeneity among these cases – including differences in primary tumor site, prior perioperative treatment, FGFR alteration status, reasons for EVP discontinuation, and platinum-based regimens – limits direct comparability.

Conclusion

After EVP therapy, PBC is commonly considered as a subsequent treatment option for mUC, except in patients with FGFR gene alterations. In this case series, PBC followed by avelumab maintenance therapy was clinically feasible and may represent a potential subsequent treatment strategy in selected patients with mUC after EVP therapy. Further studies are needed to clarify its efficacy and optimal patient selection.

Statement of Ethics

Ethical approval was not required for this case report in accordance with institutional or national guidelines. Written informed consent was obtained from the patients for the publication of this case report and any accompanying images. The authors have completed the CARE checklist, and the checklist is available as supplementary material (for all online suppl. material, see https://doi.org/10.1159/000552622).

Conflict of Interest Statement

The authors declare no conflicts of interest.

Funding Sources

This research received no external funding.

Author Contributions

Masaomi Ikeda contributed to drafting and reviewing the manuscript. Satoshi Ichikawa, Shunsuke Ito, Kazuki Okumura, and Yuriko Otsu contributed to data acquisition. Izuru Shiba, Yutaka Shiono, Soichiro Shimura, Kohei Mori, Shuhei Hirano, Dai Koguchi, Hideyasu Tsumura, Daisuke Ishii, and Kazumasa Matsumoto contributed to the conception and design of the study.

Funding Statement

This research received no external funding.

Data Availability Statement

All data related to this case series are included in this article. Further inquiries can be directed to the corresponding author.