Enfortumab Vedotin PFS May Improve Despite Specific AEs in Bladder Cancer

The FDA previously approved enfortumab vedotin with pembrolizumab for locally advanced or metastatic urothelial cancer.

The occurrence of neuropathy, skin rash, or hyperglycemia correlated with prolonged progression-free survival (PFS) among those with metastatic bladder or upper tract urothelial who received enfortumab vedotin-ejfv (Padcev), according to findings from a poster session presented at the 2025 ASCO Genitourinary Cancer Symposium.¹

After a median follow-up of 14 months from the start of enfortumab vedotin, neuropathy was reported in 30 patients (36%), skin rash in 32 patients (39%) and hyperglycemia in six patients (7%). The median PFS was 4.5 months in patients who did not experience neuropathy, skin rash or hyperglycemia; 10.6 months in those with neuropathy; 8.6 months in those with skin rash; and 15.9 months in those with hyperglycemia.

Between 2018 and 2024, a total of 83 patients were treated with at least two doses of enfortumab vedotin. Of these, 47 patients received Padcev plus pembrolizumab (Keytruda) and 36 patients received enfortumab vedotin as a single agent. The median age was 69 years. Metastatic sites included lymph nodes (42 [50%]), lungs (34 [41%]), bones (29 [35%]), liver (16 [19%]) and brain (7 [8%]). Padcev was used as first-line therapy in 43 (52%) patients, as second-line therapy in 28 (34%), as third-line therapy in 10 (12%) and as fourth-line therapy in 2 (2%).

Utilizing a query of the Indiana University bladder cancer database, investigators identified patients with locally advanced and metastatic bladder and upper tract urothelial carcinoma treated with enfortumab vedotin with or without pembrolizumab. Patients with variant histology were included. Toxicities were documented throughout treatment. The association of neuropathy, skin rash, and hyperglycemia with PFS was compared with that of patients without these side effects (SE) using the log-rank test.

“Neuropathy, skin rash, and hyperglycemia are common adverse events associated with [enfortumab vedotin],” first study author Tareq Salous, MBBS, and authors wrote in the abstract of the study.

Salous is an assistant professor of clinical medicine in the Department of Medicine, Division of Hematology/Oncology, at the Indiana University (IU) School of Medicine, IU Simon Comprehensive Cancer Center, and is an associate member of Experimental and Developmental Therapeutics, in Indianapolis.

According to the National Cancer Institute’s website, neuropathy is a nerve disorder causing pain, numbness, tingling, swelling or muscle weakness in various body parts, often starting in the hands or feet and worsening over time. It can result from cancer or cancer treatments like chemotherapy, as well as physical injury, infection, toxins or conditions such as diabetes, kidney failure or malnutrition. This is also known as peripheral neuropathy.

Furthermore, also in reference to the National Cancer Institute’s website, urothelial cancer originates in urothelial cells, which line the urethra, bladder, ureters, renal pelvis and other organs. Also known as transitional cells, these cells can change shape and stretch without breaking apart. This cancer is also referred to as transitional cell cancer.

More on the FDA Approval of This Combination

Prior to the presentation at the meeting, on December 15, 2023, the FDA approved enfortumab vedotin with pembrolizumab for locally advanced or metastatic urothelial cancer. The combination previously received accelerated approval for patients ineligible for cisplatin-based chemotherapy, according to the FDA’s website.

Approval was based on the EV-302/KN-A39 trial, an open-label, randomized study of 886 patients with locally advanced or metastatic urothelial cancer and no prior systemic therapy. Patients received either enfortumab vedotin with pembrolizumab or platinum-based chemotherapy. The primary endpoints were overall survival (OS) and PFS.

Enfortumab vedotin with pembrolizumab significantly improved OS (median 31.5 versus 16.1 months) and PFS (median 12.5 versus 6.3 months) compared with platinum-based chemotherapy.

Reference

Salous T, Hassoun R, Althouse S, Schneck S, King J, Adra N. Neuropathy, skin rash, and hyperglycemia as predictors of response to enfortumab vedotin in locally advanced and metastatic bladder and upper tract urothelial carcinoma. J Clin Oncol. 2025;43(suppl 5):771. doi:10.1200/JCO.2025.43.5_suppl.771