Oncologic outcome and safety profile of first-line enfortumab vedotin plus pembrolizumab vs. conventional chemotherapy in advanced urothelial cancer

Abstract

Aim: The aim of this multicenter study was to assess patient characteristics and short-term survival outcomes of first-line (1L) enfortumab vedotin plus pembrolizumab (EVP) as compared with conventional chemotherapy in locally advanced or metastatic urothelial carcinoma (la/mUC).

Methods: The database included 642 patients with la/mUC diagnosed between January 2008 and December 2025 at 12 collaborating hospitals. Baseline characteristics and follow-up data, including overall and organ-specific objective tumor response according to the RECIST v1.1, progression-free survival, and duration of response, were compared among the 1L regimens. Treatment-related adverse events (TRAEs) were graded according to the CTCAE v5.0 in patients treated with 1L EVP.

Results: The objective response and disease control rate were higher with 1L EVP than with chemotherapy (66% vs. 42% and 83% vs. 68%, respectively). The organ-specific response rate for liver metastatic lesions was 85%. Median progression-free survival (95% confidence interval) for 1L EVP, gemcitabine plus cisplatin, and gemcitabine plus carboplatin was 14.5 months (10.5–not determined), 10.5 months (8.4–13.3), and 9.2 months (6.7–14.2), respectively. In the safety analysis set including 40 patients, all-grade TRAEs occurred in 36 (90%) patients, including grade 1–2 events in 30 (75%) and grade 3–4 toxicities in 6 (15%). Grade 3–4 TRAEs included skin toxicity (7.5%), anorexia (5.0%), anemia (5.0%), gastrointestinal disorders (2.5%), renal dysfunction (2.5%), and interstitial lung disease (2.5%). The median number of administered EV cycles was 4 (range, 1–13), 5 (2–13), and 10 (4–13) in the overall, responder, and complete-response populations, respectively. EV dose modifications and interruptions were frequent in the initial 2 months but rare thereafter.

Conclusions: This multicenter study provides real-world evidence on short-term outcomes and safety with 1L EVP, highlighting its impact on the evolving treatment landscape for la/mUC.

Keywords

urothelial carcinoma / chemotherapy / response / outcome / enfortumab vedotin / pembrolizumab / adverse event

References

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer J Clin. 2021; 71: 209-49.

[2] Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of Bladder Cancer. Med Sci. 2020; 8: 15.

[3] Matsuda T, Okuyama A. Incidence rate for bladder cancer in Japanese in Japan and in the United States from the Cancer Incidence in Five Continents. Jpn J Clin Oncol. 2017; 47: 1-2.

[4] Liu Z, Chen C, Yin J, Cong X, Liu Z. Changing landscape of first-line treatment for locally advanced or metastatic urothelial carcinoma: the progression from platinum-based chemotherapy to platinum-free therapy. Front Immunol. 2025; 16: 1604395.

[5] Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024; 390: 875-88.

[6] Powles TB, Van der Heijden MS, Loriot Y, Bedke J, Valderrama BP, Iyer G, et al. Enfortumab vedotin plus pembrolizumab in untreated locally advanced or metastatic urothelial carcinoma: 2.5-year median follow-up of the phase III EV-302/KEYNOTE-A39 trial. Ann Oncol. 2025; 36: 1212-9.

[7] Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol. 2024; 35: 485-90.

[8] Flaig TW, Spiess PE, Abern M, Agarwal N, Bangs R, Buyyounouski MK, et al. NCCN Guidelines^® Insights: Bladder Cancer, Version 3.2024. J Natl Compr Canc Netw. 2024; 22: 216-25.

[9] EAU Guidelines Office [Internet], European Association of Urology; [cited 2026 Mar 6]. Available from: http://uroweb.org/guidelines/compilations-of-all-guidelines/

[10] van der Heijden AG, Bruins HM, Carrion A, Cathomas R, Compérat E, Dimitropoulos K, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2025 Guidelines. Eur Urol. 2025; 87: 582-600.

[11] Gupta S, Bedke J, Van Der Heijden MS, Valderrama BP, Kikuchi E, Hoffman-Censits J, et al. Exploratory analysis of responders from the phase 3 EV-302 trial of enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). J Clin Oncol. 2025; 43: 4502.

[12] Bedke J, Powles T, Valderrama BP, Gupta S, Kikuchi E, Loriot Y, et al. EV-302: Long-term subgroup analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). J Clin Oncol. 2025; 43: 4571.

[13] Kardoust Parizi M, Matsukawa A, Bekku K, Klemm J, Alimohammadi A, Laukhtina E, et al. Metastatic Organotropism Differential Treatment Response in Urothelial Carcinoma: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials. Eur Urol Oncol. 2024; 7: 663-76.

[14] Zhang S, Zhang J, Zhang Q, Liang Y, Du Y, Wang G. Identification of Prognostic Biomarkers for Bladder Cancer Based on DNA Methylation Profile. Front Cell Dev Biol. 2022; 9: 817086.

[15] Shi ZD, Han XX, Song ZJ, Dong Y, Pang K, Wang XL, et al. Integrative multi-omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD-L1 expression. Biomark Res. 2023; 11: 47.

[16] Lobo A, Collins K, Kaushal S, Acosta AM, Akgul M, Adhya AK, et al. Advances, recognition, and interpretation of molecular heterogeneity among conventional and subtype histology of urothelial carcinoma (UC): a survey among urologic pathologists and comprehensive review of the literature. Histopathology. 2024; 85: 748-59.

[17] Germanà E, Pepe L, Pizzimenti C, Ballato M, Pierconti F, Tuccari G, et al. Programmed Cell Death Ligand 1 (PD-L1) Immunohistochemical Expression in Advanced Urothelial Bladder Carcinoma: An Updated Review with Clinical and Pathological Implications. Int J Mol Sci. 2024; 25: 6750.

[18] Vellinga A, Cormican M, Hanahoe B, Bennett K, Murphy AW. Opt-out as an acceptable method of obtaining consent in medical research: a short report. BMC Med Res Methodol. 2011; 11: 40.

[19] Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised Equations for Estimated GFR From Serum Creatinine in Japan. Am J Kidney Dis. 2009; 53: 982-92.

[20] Miyake M, Nishimura N, Iemura Y, Yoshikawa M, Torimoto K, Tomioka A, et al. Impact of Initial Relative Dose Intensity on Tumor Response and Survival Outcomes in Enfortumab Vedotin Monotherapy for Previously Treated Advanced Urothelial Carcinoma: A Real-world Analysis From a Multicenter Study. Clin Genitourin Cancer. 2025; 23: 102326.

[21] Miyake M, Nishimura N, Oda Y, Shimizu T, Iida K, Fujimoto K. Real-World Analysis of the Enfortumab Vedotin-Ineligible criTeriA Assessment in Treatment-Naïve Patients With Locally Advanced or Metastatic Urothelial Carcinoma. Int J Urol. 2025; 32: 761-3.

[22] Miyake M, Shimizu T, Oda Y, Tachibana A, Ohmori C, Itami Y, et al. Switch-maintenance avelumab immunotherapy following first-line chemotherapy for patients with advanced, unresectable or metastatic urothelial carcinoma: the first Japanese real-world evidence from a multicenter study. Jpn J Clin Oncol. 2022; 53: 253-62.

[23] Pfister C, Gravis G, Flechon A, Chevreau C, Mahammedi H, Laguerre B, et al.; VESPER Trial Investigators. Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study. Lancet Oncol. 2024; 25: 255-64.

[24] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45: 228-47.

[25] Miyake M, Oda Y, Nishimura N, Yoshikawa M, Sakamoto K, Matsumura Y, et al. A Japanese Multicenter Database Study of Retroperitoneal Sarcoma: Outcomes of Patients Receiving Eribulin Therapy. Asia-Pac J Clin Oncol. 2026;[Epub ahead of print].

[26] Miyake M, Anai S, Iemura Y, Ichikawa K. A Multicenter, Single-Arm, Prospective Trial to Evaluate Efficacy and Safety of Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Carboplatin (DD-MVACarbo) Chemotherapy for Cisplatin-Ineligible Patients with Advanced Urothelial Cancer: Study Protocol of the CARBUNCLE Trial. Methods Protoc. 2024; 7: 58.

[27] Jindal T, Jiang C, Alhalabi O, Tsung I, Jang A, Bakaloudi D, et al. 1988P Enfortumab vedotin (EV) + pembrolizumab (P) outcomes outside clinical trials and biomarkers of benefit in patients (pts) with advanced urothelial carcinoma: Analysis of the UNITE study. Ann Oncol. 2024; 35: S1149-50.

[28] Zschaebitz S, Casuscelli J, Büttner T, Darr C, Volk A, Hennig M, et al. Enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma: First results on outcomes and safety in a German multicenter real-world patient cohort (GUARDIANS). J Clin Oncol. 2025; 43: 715.

[29] Niedersuess-Beke D, Mayrhofer K, Krauter J, Franke J, Vais D, Pallauf M, et al. Enfortumab vedotin plus pembrolizumab in treatment-naïve metastatic urothelial carcinoma patients: An Austrian real-world analysis. Int J Cancer. 2025; 158: 1654-65.

[30] Jain P, Naqvi SAA, Anjum MU, Khan MA, Afzal MU, Yum J, et al. Clinical efficacy of enfortumab vedotin-pembrolizumab (EV-P) in locally advanced (LA) or metastatic urothelial carcinoma (mUC): A real-world retrospective study. J Clin Oncol. 2025; 43: 745.

[31] Arbuiso A, Sternschuss M, Whiting K, Gupta A, Bent EH, Alvarez N, et al. Cutaneous toxicity and clinical outcomes with enfortumab vedotin and pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2025; 43: 4574.

[32] Kim S, Ma J, Eigl B, Alimohamed N, Kulkarni G, Chung P, et al. MP53-03 REAL-WORLD RESPONSE TO FIRST LINE PLATINUM-BASED CHEMOTHERAPY IN LOCALLY ADVANCED OR METASTATIC UROTHELIAL CARCINOMA. J Urol. 2024; 211: e211.

[33] Miyake M, Nishimura N, Oda Y, Miyamoto T, Ohmori C, Takamatsu N, et al.; Nara Urological Research and Treatment Group. Enfortumab vedotin following platinum-based chemotherapy and immune checkpoint inhibitors for advanced urothelial carcinoma: response, survival and safety analysis from a multicentre real-world Japanese cohort. Jpn J Clin Oncol. 2024; 54: 329-38.

[34] Minato A, Furubayashi N, Tomoda T, Masaoka H, Song Y, Hori Y, et al. Organ-Specific Tumor Response to Enfortumab Vedotin for Metastatic Urothelial Carcinoma: A Multicenter Retrospective Study. Clin Genitourin Cancer. 2024; 22: 102148.

[35] Yu P, Zhu C, You X, Gu W, Wang X, Wang Y, et al. The combination of immune checkpoint inhibitors and antibody-drug conjugates in the treatment of urogenital tumors: a review insights from phase 2 and 3 studies. Cell Death Dis. 2024; 15: 433.

[36] Wu Q, Li Q, Qin Y. Cost-effectiveness analysis of enfortumab vedotin and pembrolizumab versus chemotherapy for patients with untreated advanced urothelial cancer in the United Kingdom. BMJ Open. 2025; 15: e103709.

[37] Lin J, Fu W, You C, Song X, Liu M, Cai H. Updated cost-effectiveness analysis of first-line novel therapies in locally advanced or metastatic urothelial carcinoma across the UK, US, and China. World J Urol. 2025; 43: 657.

[38] Meng Y, Zhang S, Aout M, Babcock A, Li H, Lai Y, et al. Cost-effectiveness of enfortumab vedotin plus pembrolizumab as a first-line treatment of locally advanced or metastatic urothelial carcinoma in the United States. J Med Econ. 2025; 28: 1779-1797.

[39] Roberson DS, Sharma V, Boorjian SA, McLeay MT 2nd, Reitano G, Nguyen MV, et al. Consolidative Surgery for Advanced Urothelial Carcinoma Following Induction Enfortumab Vedotin and/or Immune Checkpoint Inhibitor Therapy: A Multicenter Analysis. Eur Urol. 2025; 88: 212-4.

[40] Gazzoni G, Vilbert M, Oliveira JP, Dacoregio MI, Michelon I, Reis PCA, et al. Enfortumab vedotin-related skin toxicities in patients with urothelial carcinoma: A systematic review and meta-analysis. J Clin Oncol. 2025; 43: 761.