Enfortumab Vedotin Dose Reductions May Improve Tolerability Without Impeding OS in Advanced Urothelial Carcinoma

Findings from a retrospective real-world study demonstrated that among patients with advanced urothelial carcinoma treated with the first-line combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda), up-front dose reductions of enfortumab vedotin improved tolerability without affecting overall survival (OS).¹

In the retrospective cohort study using the Flatiron Health database, 23.6% of patients initiating first-line enfortumab vedotin plus pembrolizumab (n = 496) received an up-front dose reduction; the remainder of patients began with the standard dose of the antibody-drug conjugate. According to findings published in JAMA Oncology, up-front dose reductions were associated with a 51% reduction in the risk of treatment interruption (IPTW adjusted HR, 0.49; 95% CI, 0.30-0.82; P = .007). Findings also showed that OS remained comparable between the dose-reduction cohort (n = 102) and the standard-dose cohort (n = 373; adjusted HR, 1.24; 95% CI, 0.88-1.76; P = .21).

Notably, similar results were observed in subgroup analyses of physiologically vulnerable patients (n = 213) in terms of treatment interruptions (adjusted HR, 0.49; 95% CI, 0.25-0.96; P = .04) and OS (adjusted HR, 1.15; 95% CI, 0.76-1.73; P = .49).

“These findings align with studies from other tumor types and drug classes [showing] that dose reduction may improve treatment tolerability in older patients without detrimental effects on survival outcomes,” study investigators Ryan D. Chow, MD, PhD; Ramy Sedhom, MD; and Ronac Mamtani, MD, MSC, wrote in a publication of the data. “Future pragmatic trials could investigate whether titrated EV dosing can optimize tolerability and quality of life while maintaining efficacy.”

Chow is a hematology/oncology fellow at Penn Medicine in the University of Pennsylvania Health System in Philadelphia; Mamtani is section chief of Genitourinary Cancers in the Division of Hematology-Oncology and associate professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania; and Sedhom is associate director of Penn Center for Cancer Care Innovation, clinical director of Medical Oncology, co-lead of Psychosocial Oncology Services, division chief of the Palliative Care Division, and a clinical assistant professor of medicine (Hematology-Oncology) at Penn Medicine Princeton Health.

How was this real-world analysis designed?

The retrospective study followed the December 2023 FDA approval of enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial cancer, after the combination was initially given accelerated approval in April 2023 for patients ineligible for cisplatin-containing chemotherapy.^2,3

For the retrospective study, investigators identified patients at least 18 years of age with advanced urothelial carcinoma who initiated first-line enfortumab vedotin plus pembrolizumab between April 3, 2023—corresponding to the FDA accelerated approval date—and December 31, 2024, allowing for at least 6 months of potential follow-up.¹ Patients with fewer than 30 days of follow-up based on the last documented visit date were excluded. To ensure accurate exposure assessment, investigators also excluded patients without documented enfortumab vedotin administration dosages in the MedicationAdministration table, including those with medication orders only and no recorded administrations, in accordance with Flatiron Health data curation guidance.

Up-front enfortumab vedotin dosing was classified using administered doses recorded after initiation of first-line therapy. Doses administered prior to the start of first-line treatment or without a documented administered dosage were excluded. Dose classification was based on the first 2 enfortumab vedotin administration episodes. Patient weight closest to each administration date was obtained from the Vitals table, and weight-normalized dosing was calculated in mg/kg.

Doses were rounded to the nearest 0.25 mg/kg and capped at 1.25 mg/kg, reflecting the FDA-labeled maximum dose of 125 mg; all doses at or above 125 mg were coded as 1.25 mg/kg. Patients were classified as receiving standard-dose therapy only if both of the first 2 doses were administered at 1.25 mg/kg, whereas all other dosing patterns were categorized as up-front dose reduction.

Baseline covariates included age, sex, body mass index, albumin, hemoglobin, creatinine clearance, ECOG performance status, payer type, practice setting, primary tumor site, smoking history, and surgical history, with values defined using measurements closest to treatment initiation.

Propensity scores for up-front dose reduction were estimated using an ensemble SuperLearner approach, and stabilized inverse probability of treatment weighting was applied to balance baseline characteristics between dosing groups. Weighted Cox proportional hazards models were used to evaluate OS, and competing risks models were applied to assess treatment interruption.

What were the baseline clinical characteristics of the patients included in this real-world analysis?

Baseline characteristics were reported for 496 patients, including 379 who started with standard-dose enfortumab vedotin and 117 who received an up-front reduced dose. Patients in the reduced-dose cohort had a median age of 78 years (range, 46-85) vs 72 years (range, 44-85) in the standard-dose cohort. Sex distribution was comparable between groups, with females comprising 23.0% of the standard-dose cohort and 27.4% of the reduced-dose cohort.

In the standard-dose group, 5.0% had a body mass index (BMI) of less than 18.5, 35.9% had a BMI ranging from 18.5 to 24, 35.1% had a BMI from 25 to 29, and 24.0% had a BMI of 30 or higher. In the reduced-dose group, the respective corresponding proportions 7.7%, 41.0%, 31.6%, and 19.7%.

Furthermore, albumin levels of less than 3.5 g/dL were observed in 21.4% of standard-dose patients vs 29.9% of reduced-dose patients; albumin levels of 3.5 to 3.9 g/dL occurred in 35.1% vs 42.7% of patients, respectively, and albumin levels of 4 g/dL or higher were reported in 43.5% vs 27.4% of patients, respectively. Creatinine clearance below 30 mL/min was present in 11.9% of standard-dose patients vs 18.8% of reduced-dose patients; creatinine clearance of 30 to 59 mL/min was reported in 40.4% vs 45.3% of patients, respectively; and a creatinine clearance of 60 mL/min or higher was observed in 47.7% vs 35.9% of patients, respectively. ECOG performance status of 2 or higher was more common with reduced dosing at baseline, occurring in 22.3% of patients vs 15.4% in the standard-dose group; respective rates of patients with an ECOG performance status of 0 to 1 were 77.7% and 84.6%.

Socio-demographic and practice variables were generally similar, although payer mix differed. Commercial coverage was observed in 70.7% of standard-dose patients vs 60.7% of reduced-dose patients; rates of Medicare or Medicaid were 19.8% vs 30.8%, respectively; and other or unknown payers were reported in 9.5% vs 8.5%, respectively. Most patients were treated in community settings, at 75.2% for the standard-dose cohort and 73.5% for the reduced-dose cohort.

Primary tumor site was bladder in 77.6% of standard-dose patients vs 69.2% of reduced-dose patients; nonbladder primary sites accounted for 22.4% vs 30.8% of patients, respectively. Smoking history was documented as yes in 72.8% of the standard-dose cohort vs 59.5% of the reduced-dose cohort. Prior surgery was reported in 32.7% of standard-dose patients vs 37.6% of reduced-dose patients.

References

1. Chow RD, Sedhom R, Mamtani R. Reduced-dose enfortumab vedotin, treatment continuity, and survival in urothelial cancer. JAMA Oncol. 2026;12(1):104-106. doi:10.1001/jamaoncol.2025.4566
2. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed February 3, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
3. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed February 3, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic