Promising Clinical Activity in UTUC Lesions With Enfortumab Vedotin Plus Pembrolizumab

New data from a small retrospective analysis showed activity with enfortumab vedotin and pembrolizumab in UTUC lesions.

A retrospective analysis presented at the 2025 ASCO Genitourinary Cancer Symposium highlighted the positive activity of enfortumab vedotin (EV; Padcev) monotherapy and when combined with pembrolizumab (Keytruda) in patients with upper tract urothelial carcinoma (UTUC) lesions.

The study, conducted by a team of researchers from the Johns Hopkins Departments of Medical Oncology and Urology, showed that in primary lesions for 16 patients treated with EV alone or EV plus pembrolizumab, the overall response rate (ORR) was 25% (n = 4), consisting of all partial responses. Primary lesions for an additional 10 patients showed stable disease, for a disease control rate of 87.5% (n = 14). Two patients had progressive disease.

Among all patients with measurable target lesions at baseline (n = 20) the ORR was 35% (n = 7), consisting of all partial responses. An additional 7 patients had stable disease for a disease control rate of 70% (n = 14). Six patients had progressive disease.

Study Design and Rationale

In describing the rationale for their retrospective study, the authors explained that patients with UTUC are often ineligible for standard perioperative care with cisplatin due to renal dysfunction related to disease and surgery. They added that, “Given the unprecedented activity of EV plus pembrolizumab [previously demonstrated] in advanced urothelial carcinoma, and safety in impaired renal function, the assessment of this combination in earlier disease settings for patients with UTUC is an urgent need.”

For their analysis, the researchers included patients with intact primary UTUC tumors who had received single agent EV or EV plus pembrolizumab at Johns Hopkins. They collected baseline patient characteristics through chart review. The study parameters defined primary tumor as any lesion located in the ureter and/or renal pelvis. In their poster, the researchers wrote that, “Non-measurable and sub-centimeter lesions (long axis <10mm) were deemed non-target per RECIST 1.1.” The determination of primary tumors and the calculation of overall response and other measures were conducted by 2 radiologists using RECISTv1.1 criteria.

The researchers identified 50 patients with UTUC treated with EV alone or EV plus pembrolizumab at Johns Hopkins between December 2017 and June 2024. Of these patients, 22 had intact primary tumors and were thus included in the retrospective analysis. Baseline characteristics showed that the median patient age was 72 years, 59% (n = 13) were male, and 77.3% (n = 17) were White. Tumor analysis showed that 86.4% of patients (n = 19) had pure urothelial histology and 81.8% of patients (n = 18) had visceral metastases.

Of the 22 patients with intact primary tumors, 59.1% (n = 13) received EV alone and 40.9% (n = 9) received EV plus pembrolizumab. Three patients began their EV regimen at a reduced dose. The median number of EV cycles received was 4 (range, 0.5-14). The median treatment duration was 3.3 months (range, 0.5-10).

The combination of enfortumab vedotin and pembrolizumab is currently approved by the FDA for the treatment of adult patients with locally advanced or metastatic urothelial cancer.²

In their conclusion, the researchers wrote, “Larger prospective studies are needed to assess the efficacy of this promising regimen in the perioperative setting for patients with this rare and aggressive disease.”

References

1. Vlachou E, Hoffman-Censits J, Singla N, et al. Primary tumor response to enfortumab vedotin with/without pembrolizumab in patients with upper tract urothelial cancer. J Clin Oncol. 2025;43(suppl 5):684. doi: 10.1200/JCO.2025.43.5_suppl.684
2. KEYTRUDA® (pembrolizumab) injection, for intravenous use. Initial U.S. Approval: 2014. Highlights of prescribing information. Accessed February 14, 2025. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf