Durable complete metabolic response to enfortumab vedotin plus pembrolizumab in metastatic upper tract urothelial carcinoma: a case report

Abstract

Background

Upper tract urothelial carcinoma (UTUC) accounts for approximately 5–10% of urothelial malignancies and is frequently associated with advanced stage and aggressive clinical behavior. In metastatic disease, platinum-based chemotherapy has historically represented standard first-line therapy; however, long-term outcomes remain limited. The combination of enfortumab vedotin and pembrolizumab has recently demonstrated superior survival outcomes compared with platinum-based chemotherapy in advanced urothelial carcinoma. Nevertheless, the depth and durability of response following early discontinuation of antibody–drug conjugate therapy remain incompletely characterized.

Case presentation

A 38-year-old woman with advanced UTUC developed metastatic progression involving liver, lymph nodes, peritoneum, ovary, and bone following platinum-based chemotherapy and surgery. She received three cycles of enfortumab vedotin plus pembrolizumab. Cross-sectional imaging demonstrated near-complete radiologic response with resolution of hepatic metastases and marked regression of thoracic and abdominal lymphadenopathy. Enfortumab vedotin was discontinued because of treatment-related peripheral neuropathy and dermatologic toxicity, and pembrolizumab monotherapy was continued. At the sixth cycle of pembrolizumab, FDG PET/CT revealed complete metabolic response. The patient remains progression-free for more than eight months after documentation of complete metabolic response.

Conclusion

This case demonstrates sustained complete metabolic response following short-course enfortumab vedotin combined with pembrolizumab in metastatic UTUC and highlights the potential for durable disease control despite early discontinuation of enfortumab vedotin.

Background

Upper tract urothelial carcinoma (UTUC) represents a distinct subset of urothelial malignancies arising from the renal pelvis or ureter and accounts for approximately 5–10% of all urothelial carcinomas [1]. Compared with bladder-origin disease, UTUC is more frequently diagnosed at advanced stage and is associated with inferior oncologic outcomes [1]. Importantly, patients with UTUC are often underrepresented in major urothelial carcinoma trials, and therapeutic approaches are frequently extrapolated from studies predominantly involving bladder urothelial carcinoma [1].

In metastatic settings, platinum-based chemotherapy has historically constituted the cornerstone of systemic therapy, with reported median overall survival ranging from 12 to 15 months [2]. The therapeutic landscape has evolved significantly with the introduction of antibody–drug conjugates (ADCs) and immune checkpoint inhibitors.

Enfortumab vedotin (EV) is a Nectin-4–directed ADC delivering monomethyl auristatin E (MMAE), a microtubule-disrupting cytotoxic agent. Nectin-4 is highly expressed in urothelial carcinoma, including upper tract disease [3]. In previously treated metastatic urothelial carcinoma, EV demonstrated significant survival benefit compared with chemotherapy in the phase III EV-301 trial [4]. More recently, the phase III EV-302/KEYNOTE-A39 study established enfortumab vedotin plus pembrolizumab as a superior first-line therapy compared with platinum-based chemotherapy, demonstrating improvements in overall survival, progression-free survival, and objective response rate [5]. Preclinical and clinical evidence also suggests potential synergy between EV and immune checkpoint inhibition through enhanced tumor antigen release and immune activation [6].

Although high response rates have been reported, detailed characterization of response kinetics, depth of remission, and durability after limited exposure to EV remains limited, particularly in metastatic UTUC. We present a case of sustained complete metabolic remission following short-course EV plus pembrolizumab.

Case presentation

A 38-year-old woman presented with right-sided pelvic discomfort and hydronephrosis. Imaging revealed right parailiac lymphadenopathy and distal ureteral obstruction. Baseline FDG PET/CT demonstrated intensely hypermetabolic conglomerated right iliac lymph nodes (SUVmax 13.2), suggestive of nodal metastatic involvement.

Ultrasound-guided core needle biopsy of a right parailiac lymph node revealed malignant epithelial tumor involvement. Immunohistochemical analysis demonstrated GATA-3 and p40 positivity, with CK7, CK20, and CDX2 negativity, consistent with metastatic urothelial carcinoma with squamous differentiation. Clinical and radiologic findings supported a diagnosis of upper tract urothelial carcinoma (Fig. 1).

Fig. 1.

Histopathological findings of metastatic urothelial carcinoma in a parailiac lymph node. Arrows indicate representative tumor areas and immunohistochemical positivity. A–B Malignant epithelial infiltration forming solid islands, trabecular structures, and irregular nests within a desmoplastic stroma characterized by prominent fibroblastic proliferation and dense collagenization in the lymph node parenchyma (H&E, ×20). C–D Immunohistochemical staining demonstrating nuclear expression of GATA3 and p40 in neoplastic cells

The patient initially received cisplatin plus gemcitabine chemotherapy for locally advanced upper tract urothelial carcinoma with pelvic nodal involvement. Follow-up abdominal magnetic resonance imaging demonstrated persistent right-sided pelvic disease with iliac and aortocaval lymphadenopathy, without evidence of hepatic metastases. Following multidisciplinary gynecologic oncology tumor board evaluation, surgical intervention was recommended due to persistent pelvic disease and concern for pelvic organ involvement. The patient subsequently underwent exploratory laparotomy with surgical resection and biopsy of involved tissues.

Histopathological examination demonstrated urothelial carcinoma involving the periureteral region, peritoneum, right ovary, and one regional lymph node. Immunohistochemical evaluation of the surgical specimen demonstrated PD-L1 positivity. No additional molecular or genetic analyses, including dMMR or MSI-H testing, were available. Based on prior systemic therapy and postoperative pathological findings, the disease was staged as ypT3N1M1.

Subsequent follow-up imaging demonstrated metastatic progression involving the liver, paraaortic and pelvic lymph nodes, peritoneum, ovary, and skeletal structures (Fig. 2).

Fig. 2.

Contrast-enhanced abdominal CT (a, b) and non-contrast thoracic CT (c) images obtained at the time of metastatic progression following surgery and platinum-based chemotherapy. a A heterogeneously enhancing ureteral mass invading the pelvic sidewall (arrows). b Hypovascular metastasis in the liver parenchyma (thick arrows). c Metastatic lymph nodes in the left axillary and supraclavicular regions (asterisk). U: Uterus

Following metastatic progression after platinum-based chemotherapy and surgery, systemic therapy with enfortumab vedotin plus pembrolizumab was initiated.

After three cycles of combination therapy:

• Abdominal magnetic resonance imaging demonstrated radiologic resolution of previously documented hepatic metastases and paraaortic lymphadenopathy.

• Thoracic computed tomography demonstrated resolution of a previously described spiculated pulmonary nodule and marked regression of cervical and axillary lymphadenopathy.

These findings were consistent with near-complete radiologic response according to RECIST 1.1 criteria (Fig. 3).

Fig. 3.

Post-treatment pelvic MRI (a) and contrast-enhanced thoracic and upper abdominal CT images (b, c) obtained after three cycles of enfortumab vedotin plus pembrolizumab therapy. a On contrast-enhanced fat-suppressed T1-weighted images, the previously observed pelvic mass lesion is no longer visible. b The liver metastases detected on the prior examination are not observed on the current CT images. c Previously noted axillary and supraclavicular metastatic lymph nodes are not visualized on the present examination. U: Uterus

Enfortumab vedotin was discontinued after three cycles because of clinically significant peripheral neuropathy with motor involvement and dermatologic toxicity that substantially impaired quality of life. Neurologic examination demonstrated right foot dorsiflexion weakness (3+/5), and electromyography (EMG) findings were consistent with subacute-to-chronic partial axonal degeneration predominantly affecting the fibular branch of the sciatic nerve in the right lower extremity, supporting treatment-related peripheral neuropathy. Due to persistent neurologic symptoms, enfortumab vedotin was permanently discontinued. No immune-related adverse events associated with pembrolizumab were observed, and pembrolizumab monotherapy was continued.

At the sixth cycle of pembrolizumab, follow-up FDG PET/CT demonstrated complete metabolic resolution of previously hypermetabolic nodal and visceral lesions. Skeletal lesions were metabolically inactive, and no new hypermetabolic foci were identified, findings consistent with complete metabolic response based on clinical and radiologic interpretation. Although FDG PET/CT is not universally standardized for response assessment in urothelial carcinoma, metabolic imaging provided complementary information regarding treatment response in this case. Thereafter, pembrolizumab was discontinued at the patient’s request because the treatment was not reimbursed, despite the absence of disease progression or immune-related toxicity.

Subsequent follow-up imaging confirmed continued remission. At the most recent follow-up, more than eight months after discontinuation of pembrolizumab, the patient remained in complete metabolic remission without evidence of disease progression. The overall clinical course and major treatment milestones are summarized in Fig. 4.

Fig. 4.

Timeline of the clinical course and major treatment milestones

Discussion

This case demonstrates sustained complete metabolic remission in metastatic upper tract urothelial carcinoma following short-course enfortumab vedotin combined with pembrolizumab and subsequent pembrolizumab maintenance.

Enfortumab vedotin has demonstrated clinically meaningful activity in metastatic urothelial carcinoma. In the phase III EV-301 trial, EV significantly improved overall survival compared with chemotherapy in previously treated patients [4]. Subsequently, the EV-302/KEYNOTE-A39 trial showed that EV plus pembrolizumab significantly improved overall survival and progression-free survival compared with platinum-based chemotherapy in untreated advanced urothelial carcinoma [5]. Although complete responses have been reported, detailed characterization of response depth, durability, and outcomes following early discontinuation of EV remains limited, particularly in metastatic upper tract disease, which is frequently underrepresented in major urothelial carcinoma trials [1].

Our case represents a unique clinical scenario. Based on the available preoperative clinical and radiological findings, the patient was initially managed as having locally advanced disease. Metastatic involvement was identified only on postoperative pathological examination, and the exact timing of metastatic dissemination therefore remains uncertain. In previously treated advanced urothelial carcinoma, the efficacy of enfortumab vedotin monotherapy has been established in the EV-201 and EV-301 trials [4, 7]. Although prospective evidence for enfortumab vedotin plus pembrolizumab beyond the first-line setting remains limited, recent real-world data have demonstrated meaningful clinical activity and manageable toxicity in patients receiving the combination in subsequent-line settings [8].

Emerging case reports further support the remarkable activity of this combination in urothelial carcinoma. Chan et al. reported a patient with recurrent upper tract urothelial carcinoma who achieved a pathologic complete response after neoadjuvant treatment with enfortumab vedotin plus pembrolizumab followed by nephroureterectomy [9]. Similarly, Bowen et al. described patients with plasmacytoid urothelial carcinoma, an aggressive histologic variant, who experienced meaningful and durable disease control with this combination therapy [10]. In another report, Urabe et al. documented substantial tumor regression and rapid symptomatic improvement after only two cycles of enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma [11]. These observations raise the possibility that antibody–drug conjugate–mediated cytotoxic tumor reduction may facilitate sustained antitumor immune activity during ongoing pembrolizumab maintenance [6].

Squamous differentiation in urothelial carcinoma has been associated with more aggressive clinicopathologic features and poorer oncologic outcomes in several studies, although therapeutic responsiveness remains heterogeneous [12]. In this context, the durable response observed in our patient despite squamous differentiation may be considered clinically noteworthy.

In the present case, marked tumor regression was observed after three cycles of combination therapy, with radiologic resolution of hepatic metastases and marked regression of nodal disease. Continued pembrolizumab therapy was followed by complete metabolic response on FDG PET/CT. This pattern may reflect effective cytotoxic tumor debulking followed by sustained immune-mediated tumor control under PD-1 blockade.

Metabolic imaging provided critical confirmation of response depth. While morphologic imaging demonstrated near-complete response, PET/CT confirmed absence of metabolically active disease. FDG PET/CT has been shown to provide complementary prognostic information in urothelial carcinoma and may assist in response assessment in selected cases [13].

The durability of response beyond eight months is clinically meaningful given the initial multi-organ metastatic burden and early discontinuation of EV due to treatment-related toxicity. However, conclusions should be interpreted cautiously because this report reflects the experience of a single patient. In addition, complete metabolic response was based on clinical and radiologic interpretation rather than standardized PERCIST assessment, and follow-up duration remains relatively limited.

Despite these limitations, this case contributes real-world evidence suggesting that durable disease control may be achievable after short-course EV plus pembrolizumab, even when EV must be discontinued early because of toxicity.

Conclusion

Sustained complete metabolic response was achieved in metastatic upper tract urothelial carcinoma following three cycles of enfortumab vedotin combined with pembrolizumab and continued pembrolizumab maintenance. This case highlights the potential for durable disease control despite early discontinuation of enfortumab vedotin and suggests that antibody–drug conjugate and immune checkpoint inhibitor combinations may provide meaningful clinical benefit in selected patients with advanced upper tract urothelial carcinoma.

Authors’ contributions

All authors contributed to the clinical management of the patient and preparation of the manuscript. All authors read and approved the final manuscript.

Funding

The authors received no financial support for this study.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Formal ethics committee approval was waived for this single-patient case report in accordance with institutional policy. Written informed consent for publication of the patient’s clinical details and accompanying images was obtained from the patient. This case report was conducted in accordance with the Declaration of Helsinki.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.