Management of Peripheral Neuropathy Does Not Compromise Survival Benefit With Frontline Enfortumab Vedotin/Pembrolizumab in Urothelial Cancer

Patients with metastatic urothelial carcinoma who developed treatment-emergent peripheral neuropathy following first-line treatment with enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) also experienced significant overall survival (OS) and progression-free survival (PFS) benefits compared with those who did not, according to findings from a retrospective analysis presented during the 26th Annual Meeting of the Society of Urologic Oncology.1

The HR for OS was 0.16 (95% CI, 0.05-0.58; P = .005), favoring patients who did experience peripheral neuropathy (n = 23) over those who did not (n = 18). The HR for PFS between these 2 groups was 0.22 (95% CI, 0.09-0.57; P = .071) in favor of those with peripheral neuropathy. The estimated 12-month OS rates in these respective arms were 79.8% (95% CI, 47.5%-92.8%) and 19.6% (95% CI, 3.4%-45.6%). The respective estimated 12-month PFS rates were 44.6% (95% CI, 14.3%-71.5%) and 21.1% (95% CI, 5.6%-43.2%).

“[These results] suggest that peripheral neuropathy is the ‘tax of efficacy’; patients on treatment longer, [presumably with cancer response,] are more likely to develop this exposure-related toxicity,” Ahmet Yıldırım, MD, a postdoctoral research fellow in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia, and his coauthors wrote in a poster presentation of the data. “Furthermore, the positive association between dose interruptions and survival confirms that holding therapy to manage toxicity does not compromise efficacy.”

In April 2023, the FDA granted accelerated approval to enfortumab vedotin in combination with pembrolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.2 The regulatory decision was supported by data from the phase 1/2 EV-103/KEYNOTE-869 study (NCT03288545), which showed that patients who received the doublet (n = 121) had a confirmed objective response rate (ORR) of 68% (95% CI, 59%-76%) per RECIST 1.1 criteria as assessed by blinded independent central review. The approval was expanded to include all patients with locally advanced or metastatic urothelial cancer in December 2023.3

How was the analysis conducted?

The study authors retrospectively analyzed 41 patients who received frontline enfortumab vedotin plus pembrolizumab at Winship Cancer Institute of Emory University.1 Survival outcomes were estimated via Kaplan-Meier Methods and Cox regression to assess the effect of dose interruptions on survival.

The median age of the study population was 69 years, and most patients were male (83%). A majority of patients were also White (73%), had an ECOG performance status of 0 or 1 (71%), and had urothelial histology (85%).

How did dose interruptions affect OS and PFS outcomes?

Patients who achieved an objective response were found to be significantly more likely to require a treatment break and did so earlier in their treatment course compared with non-responders. Patients who took a break from treatment (n = 20) experienced a significant OS benefit compared with those who did not (n = 21; HR, 0.30; 95% CI, 0.10-0.94; P = .039). Those who underwent a treatment break also achieved a significant PFS benefit vs those who did not (HR, 0.33; 95% CI, 0.14-0.79; P = .013).

The estimated 12-month OS rates among patients who underwent a treatment break and those who did not were 70.0% (95% CI, 36.4%-88.2%) and 27.2% (95% CI, 7.2%-52.6%), respectively. The estimated 12-month PFS rates were 47.9% (95% CI, 19.4%-71.8%) and 15.6% (95% CI, 2.7%-38.6%), respectively.

“Clinicians can manage peripheral neuropathy without compromising survival based on this retrospective study,” Yıldırım and his coauthors wrote. “Dose interruptions did not negatively impact outcomes, allowing for symptom management without sacrificing efficacy.”

References

1. Yildirim A, Rupji M, Shin D, et al. Neuropathy guides clinical decision-making and predicts survival in first-line EV+P for metastatic urothelial carcinoma. Presented at: Society of Urologic Oncology Annual Meeting; December 2-5, 2025; Phoenix, Arizona. Abstract 31.
2. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed December 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed December 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer