Introduction

Enfortumab vedotin plus pembrolizumab (EV+P) has transformed frontline treatment for metastatic urothelial carcinoma, roughly doubling median overall survival compared with platinum-based chemotherapy in the EV-302 trial. But that benefit comes with a toxicity that clinicians managing these patients need to anticipate and act on early: peripheral neuropathy. A working case illustrates how this plays out in practice and how dose modification decisions should be made.

Why Neuropathy Deserves Proactive Attention

Enfortumab vedotin is an antibody-drug conjugate targeting Nectin-4, a surface protein highly expressed on urothelial carcinoma cells. Its’ payload, monomethyl auristatin E (MMAE), is a microtubule-disrupting agent—a mechanism similar to taxanes and platinums – responsible for peripheral neuropathy. Since EV-302 established EV+P as first-line therapy for metastatic urothelial carcinoma regardless of cisplatin eligibility, and many of these patients have already received platinum-based chemotherapy with its own cumulative neuropathy risk, peripheral neuropathy is a toxicity clinicians should expect and plan for, not simply react to as it emerges.

In the EV-302 trial, the median time to onset of grade 2 or higher peripheral neuropathy was reported at 4.9 months or roughly around cycle 7, but neuropathy can emerge considerably earlier in practice, often requiring dose modification well before that point. A thorough baseline functional assessment, and early patient education about what to report, are essential before treatment begins.

Case Walkthrough: Grading and Dose Modification

A 69-year-old male with metastatic urothelial carcinoma, previously treated with platinum-based chemotherapy, was started on EV+P. Before treatment, he reported mild numbness in his fingertips that did not affect daily activities, a grade 1 peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE) grading scale.

By cycle 4, he reported worsening neuropathy affecting his ability to write checks or shop for groceries independently, increasing him to a grade 2 peripheral neuropathy as symptoms affect his instrumental activities of daily living. Per the EV prescribing information, the recommended action at this point is to hold treatment until the neuropathy resolves to grade 1 or less, then resume at the same dose. By cycle 7, however, his neuropathy had not improved to a grade 1. At this point, given he has recurrent grade 2 peripheral neuropathy, EV was dose reduced to 1 mg/kg and treatment continued. In the EV-302 trial, only about 11% of patients who developed neuropathy achieved complete resolution; the large majority, 89%, had residual neuropathy that did not fully reverse. As peripheral neuropathy is a cumulative adverse effect, providers should be particualrly aware of the potential for symptoms to develop as the duration of treatment increases. The goal is to remain on therapy as long as possible while minimizing adverse effects. Timely, early dose holds or reductions help achieve this goal. 

What to Ask, and When

Patients frequently underreport neuropathy symptoms for fear of treatment interruption. A thorough functional assessment needs to go beyond simply asking "any numbness or tingling?" and instead probe specific activities: difficulty with buttons or zippers, trouble typing or writing, problems with balance or fine motor tasks. The FACT-GOG-NTX questionnaire, developed originally for platinum and taxane-induced neuropathy in gynecologic cancers, may be a reasonable tool to extrapolate for monitoring EV-related neuropathy given the overlapping payload mechanism, though it has not been formally validated in this specific population.

Patient education should happen before neuropathy develops, not after telling patients upfront that a dose reduction is likely at some point, and that this does not mean treatment is failing, meaningfully reduces the anxiety that often drives underreporting. Emerging data suggest dose reductions do not compromise efficacy, which is reassuring to share directly with patients who are reluctant to accept a lower dose.

Practical Takeaways for the Care Team

Early detection is the single most important factor in successfully managing EV-related neuropathy over the long term. That means: a careful, specific functional assessment at every visit; using the CTCAE grading scale consistently to guide hold-versus-dose-reduce decisions; and a multidisciplinary approach, since neurology or physical therapy input can be valuable for patients with more significant functional impairment. Whether prophylactic strategies borrowed from other neuropathy-inducing regimens, such as acupuncture, might have a role in EV-related neuropathy specifically has not been studied, and should not be assumed to transfer directly from other settings.

For Patients

For patients receiving enfortumab vedotin, alone or combined with pembrolizumab, for bladder or urinary tract cancer, numbness or tingling in the hands or feet (called peripheral neuropathy) is a common side effect that tends to build gradually over several treatment cycles. It is important to tell your care team about even mild symptoms, including subtle difficulties like trouble with buttons, zippers, or handwriting, since catching this early allows for a dose adjustment that can prevent it from becoming more severe and harder to reverse. A dose reduction does not mean your treatment is not working; it is an expected part of managing this medication safely over time.

Key Takeaways

  • Peripheral neuropathy is an expected, on-target toxicity of enfortumab vedotin given its microtubule-disrupting payload and should be anticipated and monitored proactively rather than managed reactively.

  • Only about 11% of patients who develop neuropathy on EV-302 achieved complete resolution; 89% had residual symptoms, making early dose modifications invaluable.

  • A thorough, specific functional assessment (asking about buttons, zippers, handwriting, balance, ADLs) at every visit is more reliable than a general "any numbness or tingling?" question, since patients frequently underreport symptoms to avoid dose holds or reductions.

  • Proactive patient education helps set the expectation of a dose reduction before it happens, helping to reduce patient anxiety and underreporting symptoms.

References

  1. Powles TB, van der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma: the phase 3 EV-302 study. Presented at: 2026 ASCO Annual Meeting.

  2. Astellas Pharma US, Inc. and Seagen Inc. Enfortumab vedotin-ejfv (Padcev) [package insert]. U.S. Food and Drug Administration website.