Durable Complete Metabolic Response to Enfortumab Vedotin plus Pembrolizumab in Metastatic Upper Tract Urothelial Carcinoma: A Case Report

Durable Complete Metabolic Response to Enfortumab Vedotin plus Pembrolizumab in Metastatic Upper Tract Urothelial Carcinoma: A Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Durable Complete Metabolic Response to Enfortumab Vedotin plus Pembrolizumab in Metastatic Upper Tract Urothelial Carcinoma: A Case Report melike dönmez tekin, Atike Pınar Erdoğan, Mustafa Şahbazlar, Mustafa Faraşat, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9120660/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version 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 metastatic UTUC involving liver, lymph nodes, peritoneum, ovary, and bone experienced disease progression after platinum-based chemotherapy. 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 due to treatment-related adverse effects, and pembrolizumab monotherapy was continued. At the sixth cycle of pembrolizumab, FDG PET/CT revealed complete metabolic resolution of all previously hypermetabolic lesions. The patient remains progression-free for more than eight months after documentation of complete metabolic response. Conclusion: This case illustrates sustained complete metabolic remission following short-course enfortumab vedotin combined with pembrolizumab in metastatic UTUC and supports the therapeutic potential of antibody–drug conjugate and immune checkpoint inhibitor combinations in advanced disease. Complete metabolic response Enfortumab vedotin Pembrolizumab Upper tract urothelial carcinoma Figures Figure 1 Figure 2 Figure 3 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 ). 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 ). 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), consistent with metastatic disease. Ultrasound-guided core needle biopsy of a right parailiac lymph node revealed metastatic malignant epithelial tumor. 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 ). (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. Staging investigations identified metastatic involvement of the liver, paraaortic and pelvic lymph nodes, peritoneum, ovary, and skeletal structures. The patient initially received cisplatin plus gemcitabine chemotherapy. Despite treatment, disease progression occurred following surgical intervention (ypT3N1M1) (Fig. 2 ). (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. In February 2025, systemic therapy with enfortumab vedotin plus pembrolizumab was initiated. After three cycles of combination therapy: Abdominal magnetic resonance imaging demonstrated complete resolution of previously documented hepatic metastases and paraaortic lymphadenopathy. Thoracic computed tomography revealed disappearance of a previously described spiculated pulmonary nodule and regression of cervical and axillary lymphadenopathy. These findings were consistent with near-complete radiologic response according to RECIST 1.1 criteria (Fig. 3 ). (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 due to treatment-related neuropathy and dermatologic adverse effects that significantly affected quality of life. 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, consistent with complete metabolic response. Subsequent follow-up imaging confirmed continued remission. As of February 2026, the patient remains progression-free more than eight months after documentation of complete metabolic remission. Discussion This case demonstrates sustained complete metabolic remission in metastatic upper tract urothelial carcinoma following short-course enfortumab vedotin combined with pembrolizumab and continued PD-1 blockade. 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 ). Complete responses were observed in a subset of patients, although detailed characterization of response depth and durability in upper tract disease remains limited. 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 ( 6 ). 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 ( 7 ). 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 ( 8 ). These observations suggest that antibody–drug conjugate–mediated cytotoxic tumor debulking may enhance subsequent immune-mediated tumor control during continued PD-1 blockade. In the present case, rapid tumor regression was observed after three cycles of combination therapy, with resolution of hepatic metastases and nodal disease. Continued pembrolizumab therapy was associated with complete metabolic remission on 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 ( 9 ). The durability of remission beyond eight months is clinically meaningful given the initial multi-organ metastatic burden. Although randomized trials provide population-level efficacy data, detailed documentation of individual response trajectories contributes to a better understanding of response kinetics and real-world treatment outcomes. Conclusion Sustained complete metabolic remission was achieved in metastatic upper tract urothelial carcinoma following three cycles of enfortumab vedotin combined with pembrolizumab and continued pembrolizumab maintenance. This case underscores the therapeutic impact of antibody–drug conjugate and immune checkpoint inhibitor combinations in advanced urothelial carcinoma and highlights the potential for durable remission in upper tract disease. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of this case report and accompanying images. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding The authors received no financial support for this study. 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. Acknowledgements Not applicable. References Rouprêt M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. Eur Urol. 2023;84(1):49–64. 10.1016/j.eururo.2023.03.013 . Seisen T, et al. Efficacy of Systemic Chemotherapy Plus Radical Nephroureterectomy for Metastatic Upper Tract Urothelial Carcinoma. Eur Urol. 2017;71(5):714–8. 10.1016/j.eururo.2016.11.012 . Challita-Eid PM, et al. Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 2016;76(10):3003–13. 10.1158/0008-5472.CAN-15-1313 . Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125–35. 10.1056/NEJMoa2035807 . Powles T, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390(10):875–88. 10.1056/NEJMoa2312117 . Chan KH, et al. Complete Pathologic Response With Pembrolizumab and Enfortumab Vedotin in Urothelial Carcinoma of the Upper Urinary Tract. J Investig Med High Impact Case Rep. 2024 Jan-Dec;12:23247096241257333. PMID: 38804541; PMCID: PMC11135087. Bowen SG, et al. Case report series: Pembrolizumab and enfortumab vedotin in plasmacytoid urothelial carcinoma. Front Oncol. 2025;15:1608291. 10.3389/fonc.2025.1608291 . Published 2025 Sep 8. Urabe F, et al. A case of remarkable response to combined radiation therapy, enfortumab vedotin, and pembrolizumab in metastatic urothelial carcinoma. Int Cancer Conf J. 2025;14(2):143–6. 10.1007/s13691-025-00749-y . Published 2025 Jan 23. Apolo AB, et al. Clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in bladder cancer. J Clin Oncol. 2010;28(25):3973–8. 10.1200/JCO.2010.28.7052 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 26 Apr, 2026 Reviewers agreed at journal 23 Apr, 2026 Reviews received at journal 09 Apr, 2026 Reviewers agreed at journal 07 Apr, 2026 Reviewers invited by journal 07 Apr, 2026 Editor invited by journal 19 Mar, 2026 Editor assigned by journal 18 Mar, 2026 Submission checks completed at journal 18 Mar, 2026 First submitted to journal 14 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9120660","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":620743617,"identity":"63347c50-c04e-4c89-a9e3-bb3ab302ff2d","order_by":0,"name":"melike dönmez 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1","display":"","copyAsset":false,"role":"figure","size":732714,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eHistopathological findings of metastatic urothelial carcinoma in a parailiac lymph node.\u003cbr\u003e\n(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\u0026amp;E, ×20).\u003cbr\u003e\n(C–D) Immunohistochemical staining demonstrating nuclear expression of GATA3 and p40 in neoplastic cells.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9120660/v1/28800bfbddbe512532bceb0a.png"},{"id":106948184,"identity":"2607f6ee-254e-4146-8710-761fe596509c","added_by":"auto","created_at":"2026-04-15 06:59:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":284175,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePretreatment contrast-enhanced abdominal CT (a, b) and non-contrast thoracic CT (c) images.\u003cbr\u003e\n(a) A heterogeneously enhancing ureteral mass invading the pelvic sidewall (arrows).\u003cbr\u003e\n(b) Hypovascular metastasis in the liver parenchyma (thick arrows).\u003cbr\u003e\n(c) Metastatic lymph nodes in the left axillary and supraclavicular regions (asterisk).\u003cbr\u003e\nU: Uterus.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-9120660/v1/37c4be171eee907f0919f112.png"},{"id":106961161,"identity":"4b34f823-5b51-4ec6-a7e8-757a93a9d078","added_by":"auto","created_at":"2026-04-15 09:24:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":270743,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePost-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.\u003cbr\u003e\n(a) On contrast-enhanced fat-suppressed T1-weighted images, the previously observed pelvic mass lesion is no longer visible.\u003cbr\u003e\n(b) The liver metastases detected on the prior examination are not observed on the current CT images.\u003cbr\u003e\n(c) Previously noted axillary and supraclavicular metastatic lymph nodes are not visualized on the present examination.\u003cbr\u003e\nU: Uterus.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-9120660/v1/2d08c789b4bf5f0905b4ba7e.png"},{"id":106994208,"identity":"fd8e6e05-a741-4a5f-bc49-8029d1f67625","added_by":"auto","created_at":"2026-04-15 15:06:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1696750,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9120660/v1/4343bc8e-7bf3-4178-b7a6-330565a2df9f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eDurable Complete Metabolic Response to Enfortumab Vedotin plus Pembrolizumab in Metastatic Upper Tract Urothelial Carcinoma: A Case Report\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eUpper tract urothelial carcinoma (UTUC) represents a distinct subset of urothelial malignancies arising from the renal pelvis or ureter and accounts for approximately 5\u0026ndash;10% of all urothelial carcinomas (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Compared with bladder-origin disease, UTUC is more frequently diagnosed at advanced stage and is associated with inferior oncologic outcomes (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn metastatic settings, platinum-based chemotherapy has historically constituted the cornerstone of systemic therapy, with reported median overall survival ranging from 12 to 15 months (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The therapeutic landscape has evolved significantly with the introduction of antibody\u0026ndash;drug conjugates (ADCs) and immune checkpoint inhibitors.\u003c/p\u003e \u003cp\u003eEnfortumab vedotin (EV) is a Nectin-4\u0026ndash;directed ADC delivering monomethyl auristatin E (MMAE), a microtubule-disrupting cytotoxic agent. Nectin-4 is highly expressed in urothelial carcinoma, including upper tract disease (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In previously treated metastatic urothelial carcinoma, EV demonstrated significant survival benefit compared with chemotherapy in the phase III EV-301 trial (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). 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 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough 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.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 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), consistent with metastatic disease.\u003c/p\u003e \u003cp\u003eUltrasound-guided core needle biopsy of a right parailiac lymph node revealed metastatic malignant epithelial tumor. 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.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(A\u0026ndash;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\u0026amp;E, \u0026times;20).\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(C\u0026ndash;D) Immunohistochemical staining demonstrating nuclear expression of GATA3 and p40 in neoplastic cells.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eStaging investigations identified metastatic involvement of the liver, paraaortic and pelvic lymph nodes, peritoneum, ovary, and skeletal structures. The patient initially received cisplatin plus gemcitabine chemotherapy. Despite treatment, disease progression occurred following surgical intervention (ypT3N1M1) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(a) A heterogeneously enhancing ureteral mass invading the pelvic sidewall (arrows).\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(b) Hypovascular metastasis in the liver parenchyma (thick arrows).\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(c) Metastatic lymph nodes in the left axillary and supraclavicular regions (asterisk).\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eU: Uterus.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eIn February 2025, systemic therapy with enfortumab vedotin plus pembrolizumab was initiated.\u003c/p\u003e \u003cp\u003eAfter three cycles of combination therapy:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAbdominal magnetic resonance imaging demonstrated complete resolution of previously documented hepatic metastases and paraaortic lymphadenopathy.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThoracic computed tomography revealed disappearance of a previously described spiculated pulmonary nodule and regression of cervical and axillary lymphadenopathy.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThese findings were consistent with near-complete radiologic response according to RECIST 1.1 criteria (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(a) On contrast-enhanced fat-suppressed T1-weighted images, the previously observed pelvic mass lesion is no longer visible.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(b) The liver metastases detected on the prior examination are not observed on the current CT images.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003e(c) Previously noted axillary and supraclavicular metastatic lymph nodes are not visualized on the present examination.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eU: Uterus.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eEnfortumab vedotin was discontinued after three cycles due to treatment-related neuropathy and dermatologic adverse effects that significantly affected quality of life. Pembrolizumab monotherapy was continued.\u003c/p\u003e \u003cp\u003eAt 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, consistent with complete metabolic response.\u003c/p\u003e \u003cp\u003eSubsequent follow-up imaging confirmed continued remission. As of February 2026, the patient remains progression-free more than eight months after documentation of complete metabolic remission.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case demonstrates sustained complete metabolic remission in metastatic upper tract urothelial carcinoma following short-course enfortumab vedotin combined with pembrolizumab and continued PD-1 blockade.\u003c/p\u003e \u003cp\u003eEnfortumab 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 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). 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 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Complete responses were observed in a subset of patients, although detailed characterization of response depth and durability in upper tract disease remains limited.\u003c/p\u003e \u003cp\u003eEmerging 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 (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). 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 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). 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 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). These observations suggest that antibody\u0026ndash;drug conjugate\u0026ndash;mediated cytotoxic tumor debulking may enhance subsequent immune-mediated tumor control during continued PD-1 blockade.\u003c/p\u003e \u003cp\u003eIn the present case, rapid tumor regression was observed after three cycles of combination therapy, with resolution of hepatic metastases and nodal disease. Continued pembrolizumab therapy was associated with complete metabolic remission on PET/CT. This pattern may reflect effective cytotoxic tumor debulking followed by sustained immune-mediated tumor control under PD-1 blockade.\u003c/p\u003e \u003cp\u003eMetabolic 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 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe durability of remission beyond eight months is clinically meaningful given the initial multi-organ metastatic burden. Although randomized trials provide population-level efficacy data, detailed documentation of individual response trajectories contributes to a better understanding of response kinetics and real-world treatment outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSustained complete metabolic remission was achieved in metastatic upper tract urothelial carcinoma following three cycles of enfortumab vedotin combined with pembrolizumab and continued pembrolizumab maintenance. This case underscores the therapeutic impact of antibody\u0026ndash;drug conjugate and immune checkpoint inhibitor combinations in advanced urothelial carcinoma and highlights the potential for durable remission in upper tract disease.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Written informed consent was obtained from the patient for publication of this case report and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;All data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The authors received no financial support for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;All authors contributed to the clinical management of the patient and preparation of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRoupr\u0026ecirc;t M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2023 Update. Eur Urol. 2023;84(1):49\u0026ndash;64. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.eururo.2023.03.013\u003c/span\u003e\u003cspan address=\"10.1016/j.eururo.2023.03.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeisen T, et al. Efficacy of Systemic Chemotherapy Plus Radical Nephroureterectomy for Metastatic Upper Tract Urothelial Carcinoma. Eur Urol. 2017;71(5):714\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.eururo.2016.11.012\u003c/span\u003e\u003cspan address=\"10.1016/j.eururo.2016.11.012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChallita-Eid PM, et al. Enfortumab Vedotin Antibody\u0026ndash;Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 2016;76(10):3003\u0026ndash;13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/0008-5472.CAN-15-1313\u003c/span\u003e\u003cspan address=\"10.1158/0008-5472.CAN-15-1313\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePowles T, Rosenberg JE, Sonpavde GP, Loriot Y, Dur\u0026aacute;n I, Lee JL, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125\u0026ndash;35. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2035807\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2035807\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePowles T, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390(10):875\u0026ndash;88. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2312117\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2312117\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan KH, et al. Complete Pathologic Response With Pembrolizumab and Enfortumab Vedotin in Urothelial Carcinoma of the Upper Urinary Tract. J Investig Med High Impact Case Rep. 2024 Jan-Dec;12:23247096241257333. PMID: 38804541; PMCID: PMC11135087.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBowen SG, et al. Case report series: Pembrolizumab and enfortumab vedotin in plasmacytoid urothelial carcinoma. Front Oncol. 2025;15:1608291. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2025.1608291\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2025.1608291\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Published 2025 Sep 8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUrabe F, et al. A case of remarkable response to combined radiation therapy, enfortumab vedotin, and pembrolizumab in metastatic urothelial carcinoma. Int Cancer Conf J. 2025;14(2):143\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s13691-025-00749-y\u003c/span\u003e\u003cspan address=\"10.1007/s13691-025-00749-y\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Published 2025 Jan 23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eApolo AB, et al. Clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in bladder cancer. J Clin Oncol. 2010;28(25):3973\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2010.28.7052\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2010.28.7052\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"buro","sideBox":"Learn more about [BMC Urology](http://bmcurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/buro/default.aspx","title":"BMC Urology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Complete metabolic response, Enfortumab vedotin, Pembrolizumab, Upper tract urothelial carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-9120660/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9120660/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eUpper tract urothelial carcinoma (UTUC) accounts for approximately 5\u0026ndash;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\u0026ndash;drug conjugate therapy remain incompletely characterized.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eA 38-year-old woman with metastatic UTUC involving liver, lymph nodes, peritoneum, ovary, and bone experienced disease progression after platinum-based chemotherapy. 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 due to treatment-related adverse effects, and pembrolizumab monotherapy was continued. At the sixth cycle of pembrolizumab, FDG PET/CT revealed complete metabolic resolution of all previously hypermetabolic lesions. The patient remains progression-free for more than eight months after documentation of complete metabolic response.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThis case illustrates sustained complete metabolic remission following short-course enfortumab vedotin combined with pembrolizumab in metastatic UTUC and supports the therapeutic potential of antibody\u0026ndash;drug conjugate and immune checkpoint inhibitor combinations in advanced disease.\u003c/p\u003e","manuscriptTitle":"Durable Complete Metabolic Response to Enfortumab Vedotin plus Pembrolizumab in Metastatic Upper Tract Urothelial Carcinoma: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-15 06:59:26","doi":"10.21203/rs.3.rs-9120660/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-26T07:56:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308062552849404632277066059990665644577","date":"2026-04-23T14:53:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-09T13:26:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"20042536861133729215466417776680673490","date":"2026-04-07T17:56:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-07T17:15:58+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-19T20:15:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-18T14:43:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-18T14:43:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Urology","date":"2026-03-14T07:50:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-urology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"buro","sideBox":"Learn more about [BMC Urology](http://bmcurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/buro/default.aspx","title":"BMC Urology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f446e703-57f5-4690-b15c-bb8474ff4a2d","owner":[],"postedDate":"April 15th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-15T06:59:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-15 06:59:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9120660","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9120660","identity":"rs-9120660","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}