{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:49:01Z","timestamp":1790092141449,"version":"4.0.1"},"reference-count":45,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T00:00:00Z","timestamp":1699488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["F32CA254070"],"award-info":[{"award-number":["F32CA254070"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["T32CA217834"],"award-info":[{"award-number":["T32CA217834"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["K12CA090625"],"award-info":[{"award-number":["K12CA090625"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA068485"],"award-info":[{"award-number":["P30CA068485"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["S10 OD023475-01A1"],"award-info":[{"award-number":["S10 OD023475-01A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["S10 OD016355"],"award-info":[{"award-number":["S10 OD016355"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NCI\/NIH Cancer Center Support","award":["F32CA254070"],"award-info":[{"award-number":["F32CA254070"]}]},{"name":"NCI\/NIH Cancer Center Support","award":["T32CA217834"],"award-info":[{"award-number":["T32CA217834"]}]},{"name":"NCI\/NIH Cancer Center Support","award":["K12CA090625"],"award-info":[{"award-number":["K12CA090625"]}]},{"name":"NCI\/NIH Cancer Center Support","award":["P30CA068485"],"award-info":[{"award-number":["P30CA068485"]}]},{"name":"NCI\/NIH Cancer Center Support","award":["S10 OD023475-01A1"],"award-info":[{"award-number":["S10 OD023475-01A1"]}]},{"name":"NCI\/NIH Cancer Center Support","award":["S10 OD016355"],"award-info":[{"award-number":["S10 OD016355"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Penile squamous cell carcinoma is a rare disease with very limited data to guide treatment decisions. In particular, there is minimal evidence for effective therapies in the metastatic setting. Here, we present a case of metastatic penile squamous cell carcinoma with response to the Nectin-4 inhibitor enfortumab-vedotin-ejfv (EV). EV was selected due to the evidence of the high expression of Nectin-4 in squamous cell carcinomas, including penile carcinoma. The patient had both radiographic and symptomatic improvement after two cycles of treatment, despite having been treated with multiple prior lines of traditional chemotherapy. This case provides support for the use of antibody\u2013drug conjugates (ADC), including EV, in this disease with few other options in the advanced setting. Further studies examining Nectin-4 and ADCs in penile squamous cell carcinoma should be completed, as high-quality evidence is needed to guide treatment after initial progression for these patients.<\/jats:p>","DOI":"10.3390\/ijms242216109","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T03:42:08Z","timestamp":1699501328000},"page":"16109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Metastatic Penile Squamous Cell Carcinoma Responsive to Enfortumab Vedotin"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4347-361X","authenticated-orcid":false,"given":"Catherine C.","family":"Fahey","sequence":"first","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Tennessee Valley Healthcare System, Veterans\u2019 Affairs, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9402-7284","authenticated-orcid":false,"given":"Caroline A.","family":"Nebhan","sequence":"additional","affiliation":[{"name":"Intermountain Health, Murry, UT 84107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"York","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Tennessee Valley Healthcare System, Veterans\u2019 Affairs, Nashville, TN 37232, USA"},{"name":"Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy B.","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula J.","family":"Hurley","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA"},{"name":"Department of Urology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer B.","family":"Gordetsky","sequence":"additional","affiliation":[{"name":"Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA"},{"name":"Department of Urology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0097-1574","authenticated-orcid":false,"given":"Kerry R.","family":"Schaffer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s00345-008-0302-z","article-title":"Penile cancer: Epidemiology, pathogenesis and prevention","volume":"27","author":"Bleeker","year":"2009","journal-title":"World J. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1007\/s00345-019-02869-6","article-title":"Conditional survival of patients with stage I-III squamous cell carcinoma of the penis: Temporal changes in cancer-specific mortality","volume":"38","author":"Mistretta","year":"2020","journal-title":"World J. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1046\/j.1464-410X.2001.00379.x","article-title":"Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: The role and technique of lymph node dissection","volume":"88","author":"Horenblas","year":"2001","journal-title":"BJU Int."},{"key":"ref_5","unstructured":"National Comprehensive Cancer Network\u00ae (NCCN\u00ae) (2023, October 01). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines\u00ae) Penile Cancer Version 1.2023. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/penile.pdf."},{"key":"ref_6","unstructured":"ClinicalTrials.gov (2023, July 06). Available online: https:\/\/clinicaltrials.gov\/search?cond=penile%20cancer&viewType=Table."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.humpath.2019.09.013","article-title":"Morphology, p16, HPV, and outcomes in squamous cell carcinoma of the penis: A multi-institutional study","volume":"96","author":"Eich","year":"2019","journal-title":"Hum. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17588359221127254","DOI":"10.1177\/17588359221127254","article-title":"An update on treatment of penile cancer","volume":"14","author":"Chadha","year":"2022","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.euros.2022.12.008","article-title":"An Analysis of Nectin-4 (PVRL4) in Penile Squamous Cell Carcinoma","volume":"49","author":"Grass","year":"2023","journal-title":"Eur. Urol. Open Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Liu, Y., Han, X., Li, L., Zhang, Y., Huang, X., Li, G., Xu, C., Yin, M., Zhou, P., and Shi, F. (2021). Role of Nectin-4 protein in cancer (Review). Int. J. Oncol., 59.","DOI":"10.3892\/ijo.2021.5273"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e000266","DOI":"10.1136\/jitc-2019-000266","article-title":"Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity","volume":"8","author":"Reches","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1097\/PPO.0000000000000632","article-title":"Recent Advances in the Development of Antibody-Drug Conjugates in Urothelial Cancer","volume":"28","author":"Alhalabi","year":"2022","journal-title":"Cancer J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tanaka, Y., Murata, M., Oda, Y., Furue, M., and Ito, T. (2021). Nectin Cell Adhesion Molecule 4 (NECTIN4) Expression in Cutaneous Squamous Cell Carcinoma: A New Therapeutic Target?. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040355"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1007\/s11864-022-00940-w","article-title":"Nectin-4: A Novel Therapeutic Target for Skin Cancers","volume":"23","author":"Hashimoto","year":"2022","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/S1470-2045(21)00094-2","article-title":"Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): A multicentre, single-arm, phase 2 trial","volume":"22","author":"Yu","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1007\/s10637-021-01100-x","article-title":"Pembrolizumab for advanced penile cancer: A case series from a phase II basket trial","volume":"39","author":"Hahn","year":"2021","journal-title":"Investig. New Drugs"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1056\/NEJMc1713444","article-title":"Tumor Mutational Burden and Response Rate to PD-1 Inhibition","volume":"377","author":"Yarchoan","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1158\/1535-7163.MCT-17-0386","article-title":"Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers","volume":"16","author":"Goodman","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1158\/2326-6066.CIR-18-0716","article-title":"Phenotypic and Genomic Determinants of Immunotherapy Response Associated with Squamousness","volume":"1","author":"Goodman","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1111\/bju.13054","article-title":"Intermediate analysis of a phase II trial assessing gemcitabine and cisplatin in locoregional or metastatic penile squamous cell carcinoma","volume":"117","author":"Dupuy","year":"2016","journal-title":"BJU Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.urolonc.2007.10.015","article-title":"Cisplatin and gemcitabine in the management of metastatic penile cancer","volume":"27","author":"Power","year":"2009","journal-title":"Urol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.clgc.2015.08.001","article-title":"Panitumumab Treatment for Advanced Penile Squamous Cell Carcinoma When Surgery and Chemotherapy Have Failed","volume":"14","author":"Necchi","year":"2016","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S58","DOI":"10.1016\/j.urology.2010.03.082","article-title":"Treatment of visceral, unresectable, or bulky\/unresectable regional metastases of penile cancer","volume":"76","author":"Pettaway","year":"2010","journal-title":"Urology"},{"key":"ref_24","first-page":"E661","article-title":"Cisplatin and 5-fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis","volume":"110","author":"Buonerba","year":"2012","journal-title":"BJU Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.urology.2014.12.049","article-title":"Treatment for Metastatic Penile Cancer After First-line Chemotherapy Failure: Analysis of Response and Survival Outcomes","volume":"85","author":"Wang","year":"2015","journal-title":"Urology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/JCO.19.02105","article-title":"Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability\/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study","volume":"38","author":"Marabelle","year":"2020","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","volume":"357","author":"Le","year":"2017","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"615298","DOI":"10.3389\/fonc.2020.615298","article-title":"Case Report: Two Cases of Chemotherapy Refractory Metastatic Penile Squamous Cell Carcinoma With Extreme Durable Response to Pembrolizumab","volume":"10","author":"Chahoud","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Spiess, P.E., Li, R., Grivas, P., Necchi, A., Pavlick, D.C., Huang, R.S., Lin, D.I., Danziger, N., Ross, J.S., and Jacob, J.M. (2023). Bratslavsky, G. Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study. J. Clin. Oncol., 41.","DOI":"10.1200\/JCO.2023.41.6_suppl.4"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kaakour, D., Seyedin, S., Houshyar, R., and Mar, N. (2022). Combination of Pembrolizumab and Stereotactic Body Radiation Therapy in Recurrent Metastatic Penile Squamous Cell Carcinoma: A Case Study. Biomedicines, 10.","DOI":"10.3390\/biomedicines10123033"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1111\/bju.12450","article-title":"Epidermal Growth Factor Receptor\u2013Targeted Therapy in Locally Advanced or Metastatic Squamous Cell Carcinoma of the Penis","volume":"113","author":"Carthon","year":"2014","journal-title":"BJU Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/bju.14013","article-title":"First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: Results of an open-label, single-arm, single-centre, phase 2 study","volume":"121","author":"Necchi","year":"2018","journal-title":"BJU Int."},{"key":"ref_33","unstructured":"Astellas Pharma Global Development, Inc (2023, May 24). An Open-label, Multicenter, Multicohort, Phase 2 Study to Evaluate Enfortumab Vedotin in Subjects with Previously Treated Locally Advanced or Metastatic Malignant Solid Tumors (EV-202), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04225117."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13046-015-0144-7","article-title":"Nectin-4 expression contributes to tumor proliferation, angiogenesis and patient prognosis in human pancreatic cancer","volume":"34","author":"Nishiwada","year":"2015","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00432-019-03055-2","article-title":"Clinical significance of a pvrl 4 encoded gene Nectin-4 in metastasis and angiogenesis for tumor relapse","volume":"146","author":"Sethy","year":"2020","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1756287220980192","DOI":"10.1177\/1756287220980192","article-title":"Enfortumab Vedotin in urothelial cancer","volume":"12","author":"Alt","year":"2020","journal-title":"Ther. Adv. Urol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1158\/0008-5472.CAN-15-1313","article-title":"Enfortumab Vedotin Antibody\u2013Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models","volume":"76","author":"Satpayev","year":"2016","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Doronina, S.O., Toki, B.E., Torgov, M.Y., Mendelsohn, B.A., Cerveny, C.G., Chace, D.F., DeBlanc, R.L., Gearing, R.P., Bovee, T.D., and Siegall, C.B. (2003). Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat. Biotechnol., 21.","DOI":"10.1038\/nbt0803-941a"},{"key":"ref_39","unstructured":"Thomas, P. (2023, January 22). ESMO 2023: EV-302\/KEYNOTE-A39: Enfortumab Vedotin in Combination with Pembrolizumab (EV+P) Vs Chemotherapy in Previously Untreated Locally Advanced Metastatic Urothelial Carcinoma. Presented at the ESMO Congress 2023, Madrid, Spain."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.18632\/oncotarget.28299","article-title":"Nectin-4 is widely expressed in head and neck squamous cell carcinoma","volume":"13","author":"Sanders","year":"2022","journal-title":"Oncotarget"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6694","DOI":"10.1158\/0008-5472.CAN-09-0016","article-title":"Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer","volume":"69","author":"Takano","year":"2009","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Murata, M., Ito, T., Tanaka, Y., Kaku-Ito, Y., and Furue, M. (2020). NECTIN4 Expression in Extramammary Paget\u2019s Disease: Implication of a New Therapeutic Target. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165891"},{"key":"ref_43","first-page":"619","article-title":"Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes","volume":"29","author":"Lombardo","year":"2021","journal-title":"Appl. Immunohistochem. Mol. Morphol. AIMM"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Liu, B.A., Olson, D., Snead, K., Gosink, J., Tenn, E.M., Zaval, M., Cao, A., Sahetya, D., Nesterova, A., and Hensley, K. (2020). Abstract 5581: Enfortumab vedotin, an anti-Nectin-4 ADC demonstrates bystander cell killing and immunogenic cell death anti-tumor activity mechanisms of action in urothelial cancers. Cancer Res., 80.","DOI":"10.1158\/1538-7445.AM2020-5581"},{"key":"ref_45","unstructured":"Clinicaltrials.gov (2022, December 31). Phase 1\/2 Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT7480 in Patients with Nectin-4 Associated Advanced Malignancies, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05163041."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16109\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:19:45Z","timestamp":1760131185000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,9]]},"references-count":45,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216109"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216109","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,9]]}}}