Enfortumab Vedotin May Be Safe in Ultra-Elderly Patients With Urothelial Carcinoma

Findings suggested that enfortumab vedotin may not result in excessive or unexpected toxicity in ultra-elderly patients with urothelial carcinoma.

Enfortumab vedotin (Padcev) did not result in excessive or unexpected toxicity in ultra-elderly patients with urothelial carcinoma, although the sample size of this study was small and retrospective in nature, recent study findings suggest.¹

Results from this study, which were presented at the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, also demonstrated that more patients aged 85 years and older received upfront enfortumab vedotin dose reduction. Additionally, there were fewer grade 2/3 treatment-related adverse events (TRAEs) with lower starting doses of enfortumab vedotin.

“Up-front dose reduction of [enfortumab vedotin] may be a good strategy to mitigate TRAE risk,” the researchers wrote in the abstract.

The median age of the 26 patients included in this study was 86.5 years (range, 80-97). The patients were categorized by age: group 1 were aged 80 to 84 years (38.5%), group 2 were aged 85 to 89 years (46.2%), and group 3 were aged 90 years and older (15.4%). Regarding treatment, 69.2% of patients were treated with enfortumab vedotin monotherapy and 30.8% were treated with enfortumab vedotin plus pembrolizumab (Keytruda). Nearly all patients treated with enfortumab vedotin monotherapy—88.9%—previously received a PD-1/PD-L1 inhibitor.

At data cutoff, 27.0% of patients were still treated with enfortumab vedotin, with a median number of enfortumab vedotin infusions of 10.5 (range, 2-25) and a median number of weeks on the treatment of 19.5 (range, 1-52).

Starting Doses and Toxicity

The majority of patients in group 1 received an enfortumab vedotin starting dose of 1.0 mg/kg (70.0%) compared with 1.25 mg/kg (30.0%). In group 2, most patients received a starting dose of 0.75 mg/kg (41.7%), followed by 1.0 mg/kg (25.0%), 1.25 mg/kg (16.7%), and 0.5 mg/kg (16.7%). Half of the patients in group 3 received a starting dose of 1.0 mg/kg (50.0%), followed by 1.25 mg/kg (25.0%) then 0.5 mg/kg (25.0%).

After starting treatment with enfortumab vedotin, 50.0% of patients had at least 1 dose reduction, 42.3% had at least 1 delayed dose, and 30.8% had discontinued enfortumab vedotin due to TRAEs.

For toxicity, the most common severity was grade 1 (30.8%), followed by grade 0 (26.9%), grade 2 (26.9%), and grade 3 (15.4%). Of note, no patients in the study experienced grade 4/5 toxicities.

When assessed by starting dose, the percentage of patients with TRAEs related to enfortumab vedotin was highest in those who received 1.0 mg/kg (46.2%), followed by 1.25 mg/kg (23.1%), 0.75 mg/kg (19.2%), and 0.5 mg/kg (11.5%).

Some of the specific TRAEs that occurred in the study include ocular symptoms (19.2%), neuropathy (34.6%), and nausea/diarrhea (3.8% each). Additionally, pruritus, rash, abnormal electrolytes, and fatigue occurred at a rate of 15.4% each.

Background and Methods

In this retrospective analysis, researchers reviewed data from patients with urothelial carcinoma who were treated with either enfortumab vedotin monotherapy or enfortumab vedotin plus pembrolizumab. These patients were treated at 2 academic institutions in Southern California from December 2019 to September 2024. Patients were aged 80 years or older when starting treatment with enfortumab vedotin and had to receive at least 1 dose of enfortumab vedotin. Researchers graded toxicity using the CTCAE version 5 criteria.

Of the 26 patients in this analysis, 83.6% were male, 53.8% identified as Caucasian, 23.1% identified as Asian, 15.4% identified as Hispanic, and 7.7% identified as “other.”

The antibody drug conjugate enfortumab vedotin was approved by the FDA in July 2021 as monotherapy for locally advanced or metastatic urothelial cancer.² The combination of enfortumab vedotin and pembrolizumab was granted accelerated approval by the FDA in April 2023 for locally advanced or metastatic urothelial cancer.³ This was converted to a full approval in December 2023.⁴

Within the background section of the abstract, researchers noted that enfortumab vedotin was associated with several toxicities, “which are mostly nonoverlapping with those of [pembrolizumab],” they wrote.¹

Based on findings from the EV-302 study (NCT04223856), 55.9% of patients experienced grade 3 or higher TRAEs.⁵ Treatment discontinuation occurred in 35.0% of patients receiving enfortumab vedotin plus pembrolizumab.

“[Patients] aged 80 years or older (i.e., the ultra-elderly) are a special population who may be particularly vulnerable to [enfortumab vedotin] toxicity,” the researchers wrote in the abstract.¹

References

1. Mar N, Go J, Cabral MY, et al. Real world toxicity profile of enfortumab vedotin (EV) with or without pembrolizumab (P) in ultra elderly urothelial carcinoma (UC) patients (pts). J Clin Oncol. 2025;43(suppl 5):734. doi:10.1200/JCO.2025.43.5_suppl.734
2. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. News release. FDA. July 9, 2021. Accessed February 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-enfortumab-vedotin-ejfv-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 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic
4. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed February 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
5. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117.