Efficacy of Enfortumab Vedotin Ineligible criTeriA (EVITA) in advanced urothelial carcinoma

Efficacy of Enfortumab Vedotin Ineligible criTeriA (EVITA) in advanced urothelial carcinoma | 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 Article Efficacy of Enfortumab Vedotin Ineligible criTeriA (EVITA) in advanced urothelial carcinoma Takafumi Fukushima, Kazuyuki Numakura, Masanao Shiohara, Yohei Kawashima, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6198609/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Enfortumab Vedotin Ineligible criTeriA (EVITA) were proposed for the selection of patients to receive enfortumab vedotin (EV) and pembrolizumab treatment. However, the usefulness of these criteria has not been verified. We investigated the efficacy ofthe EVITA in of patients with unresectable or metastatic urothelial carcinoma (UC) who were treated with EV monotherapy in real-world practice. We retrospectively analyzed data from 301 patients with unresectableor metastatic UC who underwent first-line chemotherapy.We evaluated the numbers of patients fulfilling the EVITAand the relationship of EVITA to the safety and efficacy in patients with EV monotherapy. Of the 301 patients, 4.3% (n = 13) fulfilled the EVITA for first-line chemotherapy. The major factor contributing to a higher EVITA score was renal dysfunction. Of the 135 patients who underwent subsequent EV therapy, the number of the EVITA had no influence on the frequency of all-grade and grade ≥3 adverse events. Oncological outcomes were not associated with the number of the EVITA. In conclusion, we observed 4.3% and 14.8% of patients fulfilled the EVITA at the time of first-line and subsequent EV therapy, respectively. The efficacy of EVITA in the selection of patients for EV monotherapy could not be confirmed. Health sciences/Oncology/Cancer/Urological cancer Health sciences/Urology/Bladder Health sciences/Urology/Ureter Health sciences/Risk factors Efficacy Enfortumab vedotin EVITA Safety Urothelial carcinoma Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Management of unresectable or metastatic urothelial carcinoma (UC) has long been challenging 1 – 5 . The standard first-line treatment approach for affected patients has typically involved platinum-based chemotherapy, followed by immune checkpoint inhibitors such as pembrolizumab as a second-line option, avelumab as a maintenance therapy, and enfortumab vedotin (EV) 6 – 10 . The EV-302 trial demonstrated the efficacy of EV plus pembrolizumab (EVP) as first-line treatment 11 , and clinical practice has changed accordingly. However, because of the expected toxicity profile (especially neuropathy and skin disorders) 12 – 14 , EVP is not suitable for all patients in clinical practice 1 . The EV-Ineligible criTeriA (EVITA), which were based on the exclusion criteria of the EV-302 trial, were proposed to identify patients who may not be optimal candidates for EVP 15 . The EVITA reflect five factors: (1) hemoglobin A1c level of ≥ 8% (or baseline glucose level of > 150 mg/dL in two consecutive blood samples 1 week apart); (2) sensory or motor neuropathy grade of ≥ 2; (3) creatinine clearance or glomerular filtration rate of ≤ 45 mL/min; (4) Eastern Cooperative Oncology Group performance status (ECOG PS) score of ≥ 2; and (5) any corneal or retinal abnormality. If patients meet at least two of these criteria, they are considered ineligible for EVP treatment. However, the EVITA represent a standard based on clinical trial eligibility. Moreover, the assertion that patients who meet EVITA criteria are truly ineligible for EVP has not been validated. In particular, EV can be used safely in clinical practice when the dosage and schedule are modified 16 – 20 . Because no information about patients who fulfill EVITA is available 21 , we investigated the number of patients with unresectable or metastatic urothelial carcinoma (UC) who fulfilled the EVITA and the safety and efficacy of the EVITA in the selection of patients to receive EV monotherapy in real-world practice. Results Characteristics of the patients The median age was 73 years (IQR: 65–78). Of the 301 patients, 67 (49.6%) had upper urinary tract urothelial carcinoma, 124 (41.2%) had received local therapy, and 193 (64.1%) had distant metastases (Table 1 ). The ECOG PS and eGFR were better during first-line treatment than during the subsequent EV monotherapy. Table 1 Background of patients First-line chemotherapy Subsequent EV monotherapy Number of patients, n 301 135 Age, years (IQR) 73 (65, 78) 74 (69, 77) Male, n 217 (72.1%) 99 (73.3%) UTUC, n 144 (47.8%) 67 (49.6%) ECOG PS, n 0 220 (73.7%) 65 (48%) 1 64 (21.3%) 52 (38.5%) > 1 16 (5.3%) 18 (13.3%) Metastatic disease, n 193 (64.1%) 85 (63.0%) Local therapy, n 124 (41.2%) 81 (60.0%) eGFR, mL/min/1.72m 2 (IQR) 54 (42, 67) 45 (32, 59) EVITA population (analysis 1) Patient groups were shown in Fig. 1 . Of the 301 patients who received first-line therapy, 187 (62.1%) had an EVITA score of 0, 101 (33.6%) had an EVITA score of 1, and 13 (4.3%) had an EVITA score of ≥ 2. Of the 135 patients who underwent subsequent EV therapy, 187 (62.1%) had an EVITA score of 0, 101 (33.6%) had an EVITA score of 1, and 13 (4.3%) had an EVITA score of ≥ 2 (Fig. 2 A). The number of patients with an EVITA score of ≥ 2 was higher at the time of subsequent EV monotherapy ( n = 20 [14.8%]) than during first-line treatment. Among the 301 patients who received first-line chemotherapy, the major factor accounting for the EVITA score was an eGFR of ≤ 45 mL/min/1.73 m 2 (in 30.3% of patients), followed by an ECOG PS score of ≥ 2 (5.7%), grade ≥ 2 sensory or motor neuropathy (3.7%), and a hemoglobin A1c level of ≥ 8% (3.0%; Fig. 2 B). Among the 135 patients who received subsequent EV therapy, the proportions with an eGFR ≤ 45 mL/min/1.73 m 2 (45.2%) and grade ≥ 2 sensory or motor neuropathy (17.8%) were increased. Relationship of EVITA with safety and efficacy (analysis 2) Of the patients with any grade AEs who received EV monotherapy, 41 (91.1%) had an EVITA score of 0, 53 (75.7%) had an EVITA score of 1, and 17 (85.0%) had an EVITA score of ≥ 2. Of the patients with grade ≥ 3 AEs, 8 (17.8%) had an EVITA score of 0, 19 (27.1%) had an EVITA score of 1, and 5 (25.0%) had an EVITA score of ≥ 2 (Fig. 3 A). We found no significant association in the development of any grade and grade ≥ 3 AEs between the patients with EVITA scores of 0–1 and those with EVITA scores of ≥ 2 (P = 1.000). The effect of eGFR on the safety of EV monotherapy was not significant for any grade of AEs (83.6% with eGFRs of > 45 mL/min/1.73 m 2 vs. 80.9% with eGFRs of ≤ 45 mL/min/1.73 m 2 ; p = 0.822), grade ≥ 3 AEs (22.4% vs. 26.5%, respectively; p = 0.690), and treatment discontinuation because of AEs (9.0% vs. 13.4%, respectively; p = 0.585; Fig. 3 B). Objective response rates, including complete and partial responses, did not differ significantly between patients with EVITA scores of 0 and 1 and those with EVITA scores of ≥ 2 (Fig. 3 C). Overall survival after the initiation of EV monotherapy also did not differ significantly different between those two groups of patients (Fig. 3 D). We detected a total of 15 AE-related discontinuation cases (11.1%) as EV intolerance cases. Of the 15 patients, 2 had an EVITA score of 0 (4.4%), 9 had an EVITA score of 1 (12.9%), and 4 had an EVITA score of ≥ 2 (20.0%); the difference between the proportions of patients with EVITA scores of 0–1 and those with EVITA scores of ≥ 2 was not significant (Fig. 4 A). The association of EVITA score of ≥ 2 and AEs-related treatment discontinuation was not significant (P = 0.238; Fig. 4 B). Furthermore, the association of grade ≥ 3 AEs and AEs-related treatment discontinuation was not significant (P = 0.523; Fig. 4 C). We selected the common AEs and compared the AE profiles of patients who discontinued treatment because of AEs with those who did not. We found that fatigue was more common in patients who discontinued treatment because of AEs (40.0%) than in those who did not (Fig. 4 D). A multivariable logistic regression analysis revealed that fatigue remained a significant factor in AEs-related treatment discontinuation (OR, 3.71; 95% CI, 1.05–13.2; Fig. 4 E). Discussion In this multicenter retrospective study, we documented the proportion of patients with unresectable or metastatic UC who fulfilled the EVITA and the relationship of EVITA with the safety and efficacy subsequent EV monotherapy. We found that only a small population were ineligible for EV treatment at the time of first-line chemotherapy, but this number was 3.4-fold higher at the time of subsequent EV monotherapy. Furthermore, we found no association of EVITA with safety and efficacy. Of note is that this is the first study to validate the utility of EVITA in real-world clinical practice, and the results providing valuable information about EV ineligibility. At the time of first-line chemotherapy, 4.6% of patients fulfilled the EVITA. Because related findings have not been reported previously, it is difficult to determine whether 4.6% is a large or small proportion. Furthermore, it is meaningless to discuss the rate of EVITA without validating whether it is appropriate or not among the patients with first-line EVP therapy. The factors related to EVITA score need to be debated. The most common factor related to a high EVITA score is renal dysfunction, followed by poor ECOG PS score. We speculated that renal function (threshold of eGFR as ≤ 45 mL/min/1.73 m 2 ) may not be related to EV intolerance because eGFR of ≥ 30 mL/min/1.73 m 2 served as an eligibility threshold in the EV-302 study. We compared the safety of EV monotherapy between the patients with an eGFR of > 45 mL/min/1.73 m 2 and those whose eGFR was ≤ 45 mL/min/1.73 m 2 and found no significant differences in safety between the two groups. Furthermore, a high hemoglobin A1c level might be the risk factor for EV-related hyperglycemia, but blood glucose levels can be controlled during the process from diagnosis to initial systematic treatment, and anticancer drug treatment is started after blood glucose stabilization. For this reason, hyperglycemia at diagnosis is not considered a major contraindication to treatment. We agree that grade ≥ 2 sensory or motor neuropathy is a contraindication to EV therapy; however, affected patients do not account for a large proportion of the eligible population because only patients with serious diabetes or spinal metastases have grade ≥ 2 neuropathy at the time of first-line therapy. We could not discuss the effect of eye disorders because eye examinations were not included in our routine screening. However, no evidence suggests that patients with baseline corneal or retinal abnormalities are at an increased risk of severe eye events 21 . Therefore, we recommend that EVITA will be proposed after appropriate validation. Although this analysis concerned EV monotherapy, we found no meaningful association of EVITA with the safety and efficacy of EV. Because the EVITA was not appropriate for patient selection, we focused on AE-related treatment discontinuation as a sign of intolerance to EV. We identified 15 (11.1%) cases of intolerance to EV monotherapy, and our results suggest that fatigue is an important symptom related to tolerability. Although fatigue cannot be determined before administration, it may be an important sign of EV ineligibility. If the patient shows signs of fatigue, appropriate dosage and schedule adjustment will be important for optimal management. However, the small number of patients in this study who discontinued treatment because of AEs is a major limitation, and further investigation is necessary. Several other limitations of this study should be considered with regard to the findings. Selection bias and other unmeasurable confounders may have been introduced by the retrospective study design. The statistical analysis may have been underpowered because of the smallness of the sample. Our study was based on the results of EV monotherapy in sequential treatment, and the results may not reflect ineligibility for EVP. Despite these limitations, this study provides the foundational data for discussing the factors in EVITA, not only as first-line chemotherapy for advanced UC but also with regard to perioperative EVP therapy for muscle-invasive bladder cancer (Keynote-905/EV-303 and KEYNOTE-B15/EV-304) 22 , 23 . Larger prospective studies are necessary to obtain more robust evidence regarding the utility of EVITA in the safety and efficacy of EVP therapy. In conclusion, we observed that the number of patients who fulfilled the EVITA was low (4.3%) at the time of first-line therapy. EVITA might not be associated with safety and efficacy in patients receiving EV monotherapy. The effectiveness of the EVITA in EVP treatment needs to be validated. Methods Study design and ethics statement This retrospective, multicenter study conformed to the principles of the Declaration of Helsinki. The need for informed consent to participate was waived by an Institutional Review Board by the ethics committee of the Hirosaki University School of Medicine (approval nos. 2019-099-2 and 2021-158-2) and all participating hospitals. Written consent was not obtained from patients who decided not to participate (opt-out approach). Patient selection and evaluation We retrospectively evaluated 301 patients treated for unresectable or metastatic UC between April 2004 and December 2024. Of those, 135 were treated with EV monotherapy after first-line therapy (the EV group). Data regarding the following variables were retrieved from medical records for analysis: age, sex, ECOG PS score, tumor origin (urinary bladder or upper urinary tract), TNM stage, history of local therapy (radical cystectomy or radiotherapy), history of systemic treatment, history of sensory or motor neuropathy, and blood sampling results (serum creatinine level, estimated glomerular filtration rate [eGFR], hemoglobin A1c level, and glucose level). Tumor stage and grade were stratified according to the TNM classification (8th edition). The treatment response was evaluated according to the revised Response Evaluation Criteria in Solid Tumors guidelines, version 1.1. It was classified among the following four categories: complete response, partial response, stable disease, and progressive disease. Adverse events (AEs) were determined according to the Common Terminology Criteria for Adverse Events, version 5.0. The EVITA were defined according to five factors: (1) hemoglobin A1c level of ≥ 8% (or baseline glucose level of > 150 mg/dL in two consecutive blood samples 1 week apart); (2) sensory or motor neuropathy of grade ≥ 2; (3) creatinine clearance or glomerular filtration rate of ≤ 45 mL/min; (4) ECOG PS score of ≥ 2; and (5) any corneal or retinal abnormality. If patients met at least two of the criteria, they were considered ineligible for EVP treatment. We excluded eye disorders from the criteria because eye examination was not included in the routine screening. The number of EVITA factors (scored 0–4) was used for stratification: 0 (no factor), 1 (one factor), and ≥ 2 (two or more factors). Outcomes We determined the proportion of all patients who fulfilled the EVITA and those proportions among the patients undergoing first-line chemotherapy and those undergoing EV monotherapy (analysis 1; Fig. 1 ). Moreover, we evaluated the impact of the EVITA on the safety and efficacy of EV in patients receiving monotherapy (analysis 2; Fig. 1 ). Overall survival was defined from the time of EV monotherapy to the final follow-up or death from any cause. Statistical analyses To perform statistical analyses, we used BellCurve for Excel 4.07 (Social Survey Research Information Co. Ltd., Tokyo, Japan), GraphPad Prism 7.00 (GraphPad Software, San Diego, CA, USA), and R 4.0.2 (The R Foundation, Vienna, Austria). Data for quantitative variables were calculated as medians with interquartile ranges (IQRs). We used the Mann–Whitney U test to assess differences. Data for categorical variables were calculated as frequencies and percentages, and we used Fisher’s exact test to analyze them. A logistic regression analysis was performed to address the number of AEs involved in AE-related treatment discontinuation. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated after we controlled for potential confounders, including skin AEs, gastrointestinal AEs, neuropathy, bone marrow dysfunction, fatigue, EVITA, and grade 3 or higher AEs. We considered p values of < 0.05 indicative of statistical significance. Declarations Acknowledgments We thank Noritaka Ishii, Anna Yoneyama, Fumiya Yoneyama, Kyo Togashi, Daisuke Noro, Toshikazu Tanaka, Osamu Soma, Hirotaka Horiguchi, Shogo Hosogoe, Hiromichi Iwamura, Noriko Tokui, Yuichiro Suzuki, Kazuaki Yoshikawa, Yuki Fujita, Yukie Nishizawa, and all the participants of the Hirosaki Urological Cancer Database for their help with data collection. Funding: This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number 20K09517 to Shingo Hatakeyama). Disclosure of conflicts of interest: Shingo Hatakeyama received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Kaneka Corporation, and Nipro Corporation. The other authors have no conflicts of interest to declare. Data availability: The datasets generated and/or analyzed during the current study are not publicly available due to regulation of data usage (we do not have consent from all patients to publish this data), but are available from the corresponding author on reasonable request. Consent to Participate: Written consent was not obtained in exchange for the public disclosure of study information (opt-out approach). Consent for Publication: All authors approved for the publication. Author contributions Shingo Hatakeyama had full access to all study data and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Shingo Hatakeyama. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: Shingo Hatakeyama and Takafumi Fukushima. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: Shingo Hatakeyama. Administrative, technical, or material support: all authors. Study supervision: Chikara Ohyama. References Powles T, Bellmunt J, Comperat E, et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol . Jun 2024;35(6):485-490. doi:10.1016/j.annonc.2024.03.001 Matsumoto H, Shiraishi K, Azuma H, et al. Clinical Practice Guidelines for Bladder Cancer 2019 edition by the Japanese Urological Association: Revision working position paper. Int J Urol . 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Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study. Int J Urol . Apr 2024;31(4):342-347. doi:10.1111/iju.15368 Kita Y, Otsuka H, Ito K, et al. Real-world sequential treatment patterns and clinical outcomes among patients with advanced urothelial carcinoma in Japan. Int J Urol . May 2024;31(5):552-559. doi:10.1111/iju.15411 Taguchi S, Kawai T, Ambe Y, et al. Enfortumab vedotin versus platinum rechallenge in post-platinum, post-pembrolizumab advanced urothelial carcinoma: A multicenter propensity score-matched study. Int J Urol . Dec 2023;30(12):1180-1186. doi:10.1111/iju.15300 Uemura K, Ito H, Jikuya R, et al. Enfortumab vedotin prolongs overall survival in metastatic urothelial carcinoma following pembrolizumab therapy in real-world data. Int J Urol . Jun 2024;31(6):678-684. doi:10.1111/iju.15437 Hara T, Matsushita Y, Harada K, Fujimoto N, Fujisawa M, Miyake H. Clinical outcomes in patients with advanced urothelial carcinoma treated with enfortumab vedotin: A retrospective multicenter study in Japan. Int J Urol . Jun 2024;31(6):696-698. doi:10.1111/iju.15435 Apolo AB, Bellmunt J, Cordes L, et al. The clinical use of enfortumab vedotin and pembrolizumab in patients with advanced urothelial carcinoma: using clinical judgement over treatment criteria. ESMO Open . Sep 2024;9(9):103725. doi:10.1016/j.esmoop.2024.103725 Galsky MD, Hoimes CJ, Necchi A, et al. Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303. Future Oncol . Aug 2021;17(24):3137-3150. doi:10.2217/fon-2021-0273 Hoimes CJ, Bedke J, Loriot Y, et al. KEYNOTE-B15/EV-304: Randomized phase 3 study of perioperative enfortumab vedotin plus pembrolizumab versus chemotherapy in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC). Journal of Clinical Oncology . 2021;39(15_suppl):TPS4587-TPS4587. doi:10.1200/JCO.2021.39.15_suppl.TPS4587 Additional Declarations Competing interest reported. Shingo Hatakeyama received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Kaneka Corporation, and Nipro Corporation. The other authors have no conflicts of interest to declare. Cite Share Download PDF Status: Published Journal Publication published 18 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 25 Apr, 2025 Reviews received at journal 23 Apr, 2025 Reviews received at journal 22 Apr, 2025 Reviews received at journal 17 Apr, 2025 Reviewers agreed at journal 15 Apr, 2025 Reviewers agreed at journal 14 Apr, 2025 Reviewers agreed at journal 26 Mar, 2025 Reviewers invited by journal 25 Mar, 2025 Editor assigned by journal 25 Mar, 2025 Editor invited by journal 17 Mar, 2025 Submission checks completed at journal 17 Mar, 2025 First submitted to journal 10 Mar, 2025 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. 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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-6198609","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":434518015,"identity":"609d7cfa-98bb-4d93-866a-4f47a11ace41","order_by":0,"name":"Takafumi Fukushima","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takafumi","middleName":"","lastName":"Fukushima","suffix":""},{"id":434518016,"identity":"b6c1c3f4-8b85-4ff7-b49b-f0e0eeb192a0","order_by":1,"name":"Kazuyuki Numakura","email":"","orcid":"","institution":"Akita University Graduate School of 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yuya","middleName":"","lastName":"Sekine","suffix":""},{"id":434518021,"identity":"533e515e-0d46-4116-b3f6-055f4fc3cca0","order_by":5,"name":"Kanami Mori","email":"","orcid":"","institution":"Akita University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kanami","middleName":"","lastName":"Mori","suffix":""},{"id":434518023,"identity":"36c299d7-33dc-4f50-bbd1-f1440127e99b","order_by":6,"name":"Mizuki Kobayashi","email":"","orcid":"","institution":"Akita University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mizuki","middleName":"","lastName":"Kobayashi","suffix":""},{"id":434518024,"identity":"8b3c3350-ad3d-4295-accb-091fc3294cc6","order_by":7,"name":"Himawari Asanuma","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Himawari","middleName":"","lastName":"Asanuma","suffix":""},{"id":434518025,"identity":"d97a5493-572a-465d-be4d-784280b7366a","order_by":8,"name":"Takaki Ichiyama","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takaki","middleName":"","lastName":"Ichiyama","suffix":""},{"id":434518026,"identity":"e2a915a4-b6c6-4262-ba83-3dbe4c8cdfe9","order_by":9,"name":"Hisashi Sakurai","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hisashi","middleName":"","lastName":"Sakurai","suffix":""},{"id":434518027,"identity":"77a27ea9-3673-4121-b6c8-07e2377b67c9","order_by":10,"name":"Kai Ozaki","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kai","middleName":"","lastName":"Ozaki","suffix":""},{"id":434518028,"identity":"f112b9ca-b15b-4868-8a0e-89f697509161","order_by":11,"name":"Naoki Fujita","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Naoki","middleName":"","lastName":"Fujita","suffix":""},{"id":434518029,"identity":"6e6fb545-566a-460d-9531-e90a2d2f53d3","order_by":12,"name":"Teppei Okamoto","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Teppei","middleName":"","lastName":"Okamoto","suffix":""},{"id":434518030,"identity":"8a997b52-efef-4e05-a18b-0c8852a25ac6","order_by":13,"name":"Hayato Yamamoto","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hayato","middleName":"","lastName":"Yamamoto","suffix":""},{"id":434518032,"identity":"d9b7bc21-504f-4ef0-8eb0-cc1b9a29ef7f","order_by":14,"name":"Takahiro Yoneyama","email":"","orcid":"","institution":"Tsugaru General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Yoneyama","suffix":""},{"id":434518035,"identity":"81ec0a4c-3082-4c6e-90da-624d4c9d0549","order_by":15,"name":"Satoshi Sato","email":"","orcid":"","institution":"Ageo Central General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Sato","suffix":""},{"id":434518038,"identity":"19b81817-f951-45e6-a393-82cbe5e93153","order_by":16,"name":"Tomonori Habuchi","email":"","orcid":"","institution":"Akita University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tomonori","middleName":"","lastName":"Habuchi","suffix":""},{"id":434518040,"identity":"9ac6e3f3-60b6-463c-b7b8-6f3905871611","order_by":17,"name":"Chikara Ohyama","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chikara","middleName":"","lastName":"Ohyama","suffix":""},{"id":434518042,"identity":"b40ff43d-a5d4-45e7-82fe-d6a2bf165f30","order_by":18,"name":"Shingo Hatakeyama","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYDACCcYGIHlAzoAZzE3ggYqzEdRiTIoWMHkgcQOEm0DYXfKzm9sefqm4k76dnffhwx81aTIMEgmMH34w8OXh0mJw52C7scyZZ7k7m9mNjXmO5fAAtTBL9jCwFePUIpHYJi3Zdjh3w2E2NmkGtgoe+xsJDNJAvyQ24HLYDIiWdAOgFskf/yrAtvzGp4XhRmKb5Me2wwkgLRK8bWCHseG1xQCoRZrhzGFDoMOYjXn70ngYeB62WfYY4PaL/Iz0Z5I/Kg7LG5w/xvjwx7dkewb25MM3flQcwxliIMDMg8oHRa7BsQR8Whh/YBGswatlFIyCUTAKRhQAALYUUUSWFBnRAAAAAElFTkSuQmCC","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Hatakeyama","suffix":""}],"badges":[],"createdAt":"2025-03-10 21:38:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6198609/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6198609/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-09806-1","type":"published","date":"2025-07-18T16:05:28+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79830577,"identity":"f8cd9849-98f7-4107-bfee-b4ae6809d00a","added_by":"auto","created_at":"2025-04-03 10:23:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":377550,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy design and analysis.\u003c/strong\u003e This study included 301 patients with unresectable or metastatic urothelial carcinoma. Of the 301 patients, 135 underwent subsequent EV monotherapy. EV = enfortumab vedotin; EVITA = Enfortumab Vedotin Ineligible criTeriA.\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6198609/v1/7174c9b9506d88ac3250e387.jpg"},{"id":79831291,"identity":"944a2d5b-21b8-4a35-95f9-8c65c5972911","added_by":"auto","created_at":"2025-04-03 10:31:48","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":456000,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProportion of the EVITA population.\u003c/strong\u003e(A) Percentage of patients who met the EVITA at the time of first-line chemotherapy and subsequent EV monotherapy. (B) Factors of EVITA and their prevalence. EVITA = Enfortumab Vedotin Ineligible criTeriA.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6198609/v1/143a9766edaa55e9ed11da86.jpg"},{"id":79830587,"identity":"a7ea912c-b400-4934-90e8-85fcc8bfde47","added_by":"auto","created_at":"2025-04-03 10:23:47","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":610432,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociationof EVITA withsafety and efficacy (analysis 2).\u003c/strong\u003e (A)\u003cstrong\u003e \u003c/strong\u003eThe association of the EVITA score and adverse events (AEs). (B) The association of eGFR score and AEs. (C)The association of EVITA score and objective response rate (ORR). (D)The association of EVITA score and overall survival after EV monotherapy. eGFR = estimated glomerular filtration rate; EV= enfortumab vedotin; EVITA = Enfortumab Vedotin Ineligible criTeriA.\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6198609/v1/8eab16cf20194ba4a1468873.jpg"},{"id":79831289,"identity":"e0f63e06-fec3-4fe0-9e6c-f0a90ef36c11","added_by":"auto","created_at":"2025-04-03 10:31:46","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":580430,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFactors associated with adverse event (AE)–related EV discontinuation.\u003c/strong\u003e(A)The association of EVITA score and AE-related EV discontinuation. (B) The association of EVITA score ≥2 and AE-related EV discontinuation. (C) The association of grade ≥3 AE and AE-related EV discontinuation. (D)EV discontinuation because ofmajor AEs. (E)Logistic regression analysis for major AE-relatedEV discontinuation.EV = enfortumab vedotin; EVITA = Enfortumab Vedotin Ineligible criTeriA.\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6198609/v1/a6ab1e03352c43a0667fd332.jpg"},{"id":88505961,"identity":"8c995ad3-7f2b-40d2-b154-a1da08786318","added_by":"auto","created_at":"2025-08-07 07:29:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2779409,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6198609/v1/67fadc69-4f9c-4f58-a8e9-94e662577041.pdf"}],"financialInterests":"Competing interest reported. Shingo Hatakeyama received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Kaneka Corporation, and Nipro Corporation. The other authors have no conflicts of interest to declare.","formattedTitle":"Efficacy of Enfortumab Vedotin Ineligible criTeriA (EVITA) in advanced urothelial carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eManagement of unresectable or metastatic urothelial carcinoma (UC) has long been challenging \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The standard first-line treatment approach for affected patients has typically involved platinum-based chemotherapy, followed by immune checkpoint inhibitors such as pembrolizumab as a second-line option, avelumab as a maintenance therapy, and enfortumab vedotin (EV) \u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The EV-302 trial demonstrated the efficacy of EV plus pembrolizumab (EVP) as first-line treatment \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, and clinical practice has changed accordingly. However, because of the expected toxicity profile (especially neuropathy and skin disorders)\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, EVP is not suitable for all patients in clinical practice \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The EV-Ineligible criTeriA (EVITA), which were based on the exclusion criteria of the EV-302 trial, were proposed to identify patients who may not be optimal candidates for EVP \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The EVITA reflect five factors: (1) hemoglobin A1c level of \u0026ge;\u0026thinsp;8% (or baseline glucose level of \u0026gt;\u0026thinsp;150 mg/dL in two consecutive blood samples 1 week apart); (2) sensory or motor neuropathy grade of \u0026ge;\u0026thinsp;2; (3) creatinine clearance or glomerular filtration rate of \u0026le;\u0026thinsp;45 mL/min; (4) Eastern Cooperative Oncology Group performance status (ECOG PS) score of \u0026ge;\u0026thinsp;2; and (5) any corneal or retinal abnormality. If patients meet at least two of these criteria, they are considered ineligible for EVP treatment. However, the EVITA represent a standard based on clinical trial eligibility. Moreover, the assertion that patients who meet EVITA criteria are truly ineligible for EVP has not been validated. In particular, EV can be used safely in clinical practice when the dosage and schedule are modified \u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Because no information about patients who fulfill EVITA is available \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, we investigated the number of patients with unresectable or metastatic urothelial carcinoma (UC) who fulfilled the EVITA and the safety and efficacy of the EVITA in the selection of patients to receive EV monotherapy in real-world practice.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the patients\u003c/h2\u003e \u003cp\u003eThe median age was 73 years (IQR: 65\u0026ndash;78). Of the 301 patients, 67 (49.6%) had upper urinary tract urothelial carcinoma, 124 (41.2%) had received local therapy, and 193 (64.1%) had distant metastases (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The ECOG PS and eGFR were better during first-line treatment than during the subsequent EV monotherapy.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBackground of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFirst-line \u003c/p\u003e \u003cp\u003echemotherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSubsequent \u003c/p\u003e \u003cp\u003eEV monotherapy\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of patients, n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e301\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years (IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (65, 78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (69, 77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale, n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e217 (72.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99 (73.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUTUC, n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e144 (47.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (49.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG PS, n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e220 (73.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (48%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (21.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (38.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (13.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetastatic disease, n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e193 (64.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85 (63.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLocal therapy, n\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e124 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81 (60.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGFR, mL/min/1.72m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e(IQR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (42, 67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (32, 59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEVITA population (analysis 1)\u003c/h3\u003e\n\u003cp\u003ePatient groups were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Of the 301 patients who received first-line therapy, 187 (62.1%) had an EVITA score of 0, 101 (33.6%) had an EVITA score of 1, and 13 (4.3%) had an EVITA score of \u0026ge;\u0026thinsp;2. Of the 135 patients who underwent subsequent EV therapy, 187 (62.1%) had an EVITA score of 0, 101 (33.6%) had an EVITA score of 1, and 13 (4.3%) had an EVITA score of \u0026ge;\u0026thinsp;2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The number of patients with an EVITA score of \u0026ge;\u0026thinsp;2 was higher at the time of subsequent EV monotherapy (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;20 [14.8%]) than during first-line treatment. Among the 301 patients who received first-line chemotherapy, the major factor accounting for the EVITA score was an eGFR of \u0026le;\u0026thinsp;45 mL/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (in 30.3% of patients), followed by an ECOG PS score of \u0026ge;\u0026thinsp;2 (5.7%), grade\u0026thinsp;\u0026ge;\u0026thinsp;2 sensory or motor neuropathy (3.7%), and a hemoglobin A1c level of \u0026ge;\u0026thinsp;8% (3.0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Among the 135 patients who received subsequent EV therapy, the proportions with an eGFR\u0026thinsp;\u0026le;\u0026thinsp;45 mL/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (45.2%) and grade\u0026thinsp;\u0026ge;\u0026thinsp;2 sensory or motor neuropathy (17.8%) were increased.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eRelationship of EVITA with safety and efficacy (analysis 2)\u003c/h3\u003e\n\u003cp\u003eOf the patients with any grade AEs who received EV monotherapy, 41 (91.1%) had an EVITA score of 0, 53 (75.7%) had an EVITA score of 1, and 17 (85.0%) had an EVITA score of \u0026ge;\u0026thinsp;2. Of the patients with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs, 8 (17.8%) had an EVITA score of 0, 19 (27.1%) had an EVITA score of 1, and 5 (25.0%) had an EVITA score of \u0026ge;\u0026thinsp;2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). We found no significant association in the development of any grade and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs between the patients with EVITA scores of 0\u0026ndash;1 and those with EVITA scores of \u0026ge;\u0026thinsp;2 (P\u0026thinsp;=\u0026thinsp;1.000). The effect of eGFR on the safety of EV monotherapy was not significant for any grade of AEs (83.6% with eGFRs of \u0026gt;\u0026thinsp;45 mL/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e vs. 80.9% with eGFRs of \u0026le;\u0026thinsp;45 mL/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.822), grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs (22.4% vs. 26.5%, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.690), and treatment discontinuation because of AEs (9.0% vs. 13.4%, respectively; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.585; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Objective response rates, including complete and partial responses, did not differ significantly between patients with EVITA scores of 0 and 1 and those with EVITA scores of \u0026ge;\u0026thinsp;2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Overall survival after the initiation of EV monotherapy also did not differ significantly different between those two groups of patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe detected a total of 15 AE-related discontinuation cases (11.1%) as EV intolerance cases. Of the 15 patients, 2 had an EVITA score of 0 (4.4%), 9 had an EVITA score of 1 (12.9%), and 4 had an EVITA score of \u0026ge;\u0026thinsp;2 (20.0%); the difference between the proportions of patients with EVITA scores of 0\u0026ndash;1 and those with EVITA scores of \u0026ge;\u0026thinsp;2 was not significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). The association of EVITA score of \u0026ge;\u0026thinsp;2 and AEs-related treatment discontinuation was not significant (P\u0026thinsp;=\u0026thinsp;0.238; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). Furthermore, the association of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs and AEs-related treatment discontinuation was not significant (P\u0026thinsp;=\u0026thinsp;0.523; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). We selected the common AEs and compared the AE profiles of patients who discontinued treatment because of AEs with those who did not. We found that fatigue was more common in patients who discontinued treatment because of AEs (40.0%) than in those who did not (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD). A multivariable logistic regression analysis revealed that fatigue remained a significant factor in AEs-related treatment discontinuation (OR, 3.71; 95% CI, 1.05\u0026ndash;13.2; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this multicenter retrospective study, we documented the proportion of patients with unresectable or metastatic UC who fulfilled the EVITA and the relationship of EVITA with the safety and efficacy subsequent EV monotherapy. We found that only a small population were ineligible for EV treatment at the time of first-line chemotherapy, but this number was 3.4-fold higher at the time of subsequent EV monotherapy. Furthermore, we found no association of EVITA with safety and efficacy. Of note is that this is the first study to validate the utility of EVITA in real-world clinical practice, and the results providing valuable information about EV ineligibility.\u003c/p\u003e \u003cp\u003eAt the time of first-line chemotherapy, 4.6% of patients fulfilled the EVITA. Because related findings have not been reported previously, it is difficult to determine whether 4.6% is a large or small proportion. Furthermore, it is meaningless to discuss the rate of EVITA without validating whether it is appropriate or not among the patients with first-line EVP therapy.\u003c/p\u003e \u003cp\u003eThe factors related to EVITA score need to be debated. The most common factor related to a high EVITA score is renal dysfunction, followed by poor ECOG PS score. We speculated that renal function (threshold of eGFR as \u0026le;\u0026thinsp;45 mL/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e) may not be related to EV intolerance because eGFR of \u0026ge;\u0026thinsp;30 mL/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e served as an eligibility threshold in the EV-302 study. We compared the safety of EV monotherapy between the patients with an eGFR of \u0026gt;\u0026thinsp;45 mL/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and those whose eGFR was \u0026le;\u0026thinsp;45 mL/min/1.73 m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and found no significant differences in safety between the two groups. Furthermore, a high hemoglobin A1c level might be the risk factor for EV-related hyperglycemia, but blood glucose levels can be controlled during the process from diagnosis to initial systematic treatment, and anticancer drug treatment is started after blood glucose stabilization. For this reason, hyperglycemia at diagnosis is not considered a major contraindication to treatment. We agree that grade\u0026thinsp;\u0026ge;\u0026thinsp;2 sensory or motor neuropathy is a contraindication to EV therapy; however, affected patients do not account for a large proportion of the eligible population because only patients with serious diabetes or spinal metastases have grade\u0026thinsp;\u0026ge;\u0026thinsp;2 neuropathy at the time of first-line therapy. We could not discuss the effect of eye disorders because eye examinations were not included in our routine screening. However, no evidence suggests that patients with baseline corneal or retinal abnormalities are at an increased risk of severe eye events \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Therefore, we recommend that EVITA will be proposed after appropriate validation.\u003c/p\u003e \u003cp\u003eAlthough this analysis concerned EV monotherapy, we found no meaningful association of EVITA with the safety and efficacy of EV. Because the EVITA was not appropriate for patient selection, we focused on AE-related treatment discontinuation as a sign of intolerance to EV. We identified 15 (11.1%) cases of intolerance to EV monotherapy, and our results suggest that fatigue is an important symptom related to tolerability. Although fatigue cannot be determined before administration, it may be an important sign of EV ineligibility. If the patient shows signs of fatigue, appropriate dosage and schedule adjustment will be important for optimal management. However, the small number of patients in this study who discontinued treatment because of AEs is a major limitation, and further investigation is necessary.\u003c/p\u003e \u003cp\u003eSeveral other limitations of this study should be considered with regard to the findings. Selection bias and other unmeasurable confounders may have been introduced by the retrospective study design. The statistical analysis may have been underpowered because of the smallness of the sample. Our study was based on the results of EV monotherapy in sequential treatment, and the results may not reflect ineligibility for EVP. Despite these limitations, this study provides the foundational data for discussing the factors in EVITA, not only as first-line chemotherapy for advanced UC but also with regard to perioperative EVP therapy for muscle-invasive bladder cancer (Keynote-905/EV-303 and KEYNOTE-B15/EV-304) \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Larger prospective studies are necessary to obtain more robust evidence regarding the utility of EVITA in the safety and efficacy of EVP therapy.\u003c/p\u003e \u003cp\u003eIn conclusion, we observed that the number of patients who fulfilled the EVITA was low (4.3%) at the time of first-line therapy. EVITA might not be associated with safety and efficacy in patients receiving EV monotherapy. The effectiveness of the EVITA in EVP treatment needs to be validated.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and ethics statement\u003c/h2\u003e \u003cp\u003e This retrospective, multicenter study conformed to the principles of the Declaration of Helsinki. The need for informed consent to participate was waived by an Institutional Review Board by the ethics committee of the Hirosaki University School of Medicine (approval nos. 2019-099-2 and 2021-158-2) and all participating hospitals. Written consent was not obtained from patients who decided not to participate (opt-out approach).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient selection and evaluation\u003c/h3\u003e\n\u003cp\u003eWe retrospectively evaluated 301 patients treated for unresectable or metastatic UC between April 2004 and December 2024. Of those, 135 were treated with EV monotherapy after first-line therapy (the EV group). Data regarding the following variables were retrieved from medical records for analysis: age, sex, ECOG PS score, tumor origin (urinary bladder or upper urinary tract), TNM stage, history of local therapy (radical cystectomy or radiotherapy), history of systemic treatment, history of sensory or motor neuropathy, and blood sampling results (serum creatinine level, estimated glomerular filtration rate [eGFR], hemoglobin A1c level, and glucose level). Tumor stage and grade were stratified according to the TNM classification (8th edition). The treatment response was evaluated according to the revised Response Evaluation Criteria in Solid Tumors guidelines, version 1.1. It was classified among the following four categories: complete response, partial response, stable disease, and progressive disease. Adverse events (AEs) were determined according to the Common Terminology Criteria for Adverse Events, version 5.0.\u003c/p\u003e \u003cp\u003eThe EVITA were defined according to five factors: (1) hemoglobin A1c level of \u0026ge;\u0026thinsp;8% (or baseline glucose level of \u0026gt;\u0026thinsp;150 mg/dL in two consecutive blood samples 1 week apart); (2) sensory or motor neuropathy of grade\u0026thinsp;\u0026ge;\u0026thinsp;2; (3) creatinine clearance or glomerular filtration rate of \u0026le;\u0026thinsp;45 mL/min; (4) ECOG PS score of \u0026ge;\u0026thinsp;2; and (5) any corneal or retinal abnormality. If patients met at least two of the criteria, they were considered ineligible for EVP treatment. We excluded eye disorders from the criteria because eye examination was not included in the routine screening. The number of EVITA factors (scored 0\u0026ndash;4) was used for stratification: 0 (no factor), 1 (one factor), and \u0026ge;\u0026thinsp;2 (two or more factors).\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eWe determined the proportion of all patients who fulfilled the EVITA and those proportions among the patients undergoing first-line chemotherapy and those undergoing EV monotherapy (analysis 1; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Moreover, we evaluated the impact of the EVITA on the safety and efficacy of EV in patients receiving monotherapy (analysis 2; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Overall survival was defined from the time of EV monotherapy to the final follow-up or death from any cause.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eTo perform statistical analyses, we used BellCurve for Excel 4.07 (Social Survey Research Information Co. Ltd., Tokyo, Japan), GraphPad Prism 7.00 (GraphPad Software, San Diego, CA, USA), and R 4.0.2 (The R Foundation, Vienna, Austria). Data for quantitative variables were calculated as medians with interquartile ranges (IQRs). We used the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test to assess differences. Data for categorical variables were calculated as frequencies and percentages, and we used Fisher\u0026rsquo;s exact test to analyze them. A logistic regression analysis was performed to address the number of AEs involved in AE-related treatment discontinuation. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated after we controlled for potential confounders, including skin AEs, gastrointestinal AEs, neuropathy, bone marrow dysfunction, fatigue, EVITA, and grade 3 or higher AEs. We considered \u003cem\u003ep\u003c/em\u003e values of \u0026lt;\u0026thinsp;0.05 indicative of statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Noritaka Ishii, Anna Yoneyama, Fumiya Yoneyama, Kyo Togashi,\u0026nbsp;Daisuke Noro, Toshikazu Tanaka, Osamu Soma, Hirotaka Horiguchi, Shogo Hosogoe, Hiromichi Iwamura, Noriko Tokui, Yuichiro Suzuki, Kazuaki Yoshikawa, Yuki Fujita, Yukie Nishizawa, and all the participants of the Hirosaki Urological Cancer Database for their help with data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number 20K09517 to Shingo Hatakeyama).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of conflicts of interest:\u003c/strong\u003e Shingo Hatakeyama received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Kaneka Corporation, and Nipro Corporation. The other authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to regulation of data usage (we do not have consent from all patients to publish this data), but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate:\u0026nbsp;\u003c/strong\u003eWritten consent was not obtained in exchange for the public disclosure of study information (opt-out approach).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication:\u0026nbsp;\u003c/strong\u003eAll authors approved for the publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShingo Hatakeyama had full access to all study data and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Shingo Hatakeyama. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: Shingo Hatakeyama and Takafumi Fukushima. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: Shingo Hatakeyama. Administrative, technical, or material support: all authors. Study supervision: Chikara Ohyama.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003ePowles T, Bellmunt J, Comperat E, et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. \u003cem\u003eAnn Oncol\u003c/em\u003e. Jun 2024;35(6):485-490. doi:10.1016/j.annonc.2024.03.001\u003c/li\u003e\n \u003cli\u003eMatsumoto H, Shiraishi K, Azuma H, et al. Clinical Practice Guidelines for Bladder Cancer 2019 edition by the Japanese Urological Association: Revision working position paper. \u003cem\u003eInt J Urol\u003c/em\u003e. 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Enfortumab vedotin prolongs overall survival in metastatic urothelial carcinoma following pembrolizumab therapy in real-world data. \u003cem\u003eInt J Urol\u003c/em\u003e. Jun 2024;31(6):678-684. doi:10.1111/iju.15437\u003c/li\u003e\n \u003cli\u003eHara T, Matsushita Y, Harada K, Fujimoto N, Fujisawa M, Miyake H. Clinical outcomes in patients with advanced urothelial carcinoma treated with enfortumab vedotin: A retrospective multicenter study in Japan. \u003cem\u003eInt J Urol\u003c/em\u003e. Jun 2024;31(6):696-698. doi:10.1111/iju.15435\u003c/li\u003e\n \u003cli\u003eApolo AB, Bellmunt J, Cordes L, et al. The clinical use of enfortumab vedotin and pembrolizumab in patients with advanced urothelial carcinoma: using clinical judgement over treatment criteria. \u003cem\u003eESMO Open\u003c/em\u003e. Sep 2024;9(9):103725. doi:10.1016/j.esmoop.2024.103725\u003c/li\u003e\n \u003cli\u003eGalsky MD, Hoimes CJ, Necchi A, et al. Perioperative pembrolizumab therapy in muscle-invasive bladder cancer: Phase III KEYNOTE-866 and KEYNOTE-905/EV-303. \u003cem\u003eFuture Oncol\u003c/em\u003e. Aug 2021;17(24):3137-3150. doi:10.2217/fon-2021-0273\u003c/li\u003e\n \u003cli\u003eHoimes CJ, Bedke J, Loriot Y, et al. KEYNOTE-B15/EV-304: Randomized phase 3 study of perioperative enfortumab vedotin plus pembrolizumab versus chemotherapy in cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC). \u003cem\u003eJournal of Clinical Oncology\u003c/em\u003e. 2021;39(15_suppl):TPS4587-TPS4587. doi:10.1200/JCO.2021.39.15_suppl.TPS4587\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Efficacy, Enfortumab vedotin, EVITA, Safety, Urothelial carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-6198609/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6198609/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEnfortumab Vedotin Ineligible criTeriA (EVITA) were proposed for the selection of patients to receive enfortumab vedotin (EV) and pembrolizumab treatment. However, the usefulness of these criteria has not been verified. We investigated the efficacy ofthe EVITA in of patients with unresectable or metastatic urothelial carcinoma (UC) who were treated with EV monotherapy in real-world practice. We retrospectively analyzed data from 301 patients with unresectableor metastatic UC who underwent first-line chemotherapy.We evaluated the numbers of patients fulfilling the EVITAand the relationship of EVITA to the safety and efficacy in patients with EV monotherapy. Of the 301 patients, 4.3% (n = 13) fulfilled the EVITA for first-line chemotherapy. The major factor contributing to a higher EVITA score was renal dysfunction. Of the 135 patients who underwent subsequent EV therapy, the number of the EVITA had no influence on the frequency of all-grade and grade ≥3 adverse events. Oncological outcomes were not associated with the number of the EVITA. In conclusion, we observed 4.3% and 14.8% of patients fulfilled the EVITA at the time of first-line and subsequent EV therapy, respectively. The efficacy of EVITA in the selection of patients for EV monotherapy could not be confirmed.\u003c/p\u003e","manuscriptTitle":"Efficacy of Enfortumab Vedotin Ineligible criTeriA (EVITA) in advanced urothelial carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-03 10:23:30","doi":"10.21203/rs.3.rs-6198609/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-25T07:15:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-23T10:36:27+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-22T05:11:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-18T03:33:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"249430259604559449734805612175336904286","date":"2025-04-15T12:36:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"116527466685118028389032295726507918622","date":"2025-04-14T10:36:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"285540123449387940266278831399369024024","date":"2025-03-26T22:48:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-25T06:47:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-25T06:39:24+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-17T09:28:43+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-17T04:52:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-03-10T21:35:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0f1188c0-a3c5-4432-9e7f-ab3aab81916f","owner":[],"postedDate":"April 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46269182,"name":"Health sciences/Oncology/Cancer/Urological cancer"},{"id":46269183,"name":"Health sciences/Urology/Bladder"},{"id":46269184,"name":"Health sciences/Urology/Ureter"},{"id":46269185,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-08-07T07:11:04+00:00","versionOfRecord":{"articleIdentity":"rs-6198609","link":"https://doi.org/10.1038/s41598-025-09806-1","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-18 16:05:28","publishedOnDateReadable":"July 18th, 2025"},"versionCreatedAt":"2025-04-03 10:23:30","video":"","vorDoi":"10.1038/s41598-025-09806-1","vorDoiUrl":"https://doi.org/10.1038/s41598-025-09806-1","workflowStages":[]},"version":"v1","identity":"rs-6198609","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6198609","identity":"rs-6198609","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}