Complete Response to Enfortumab Vedotin in a Hemodialysis Patient with Metastatic Urothelial Carcinoma: A Case Report

Abstract

Enfortumab vedotin (EV) is an antibody-drug conjugate and a promising agent for metastatic urothelial carcinoma (mUC). However, evaluations in end-stage renal disease patients undergoing hemodialysis are unreported. Here, we report such a case. A 74-year-old woman with mUC, on hemodialysis for complete urinary tract extirpation, was diagnosed with multiple pulmonary metastases after treatment with gemcitabine-carboplatin followed by pembrolizumab. As third-line therapy, she received a standard dose of EV. She achieved complete response after 2 cycles without grade 3 or higher adverse events, demonstrating the utility of EV in this setting.

Introduction

Platinum-based chemotherapy and immune checkpoint inhibitors are the current standard of care for metastatic urothelial carcinoma (mUC). Although platinum-based chemotherapy offers a promising initial response, adverse events are difficult to manage and only limited patients receive a sustained benefit from platinum-based chemotherapy. Immune checkpoint inhibitors have improved survival in different settings for mUC patients, but the efficacy remains insufficient [1, 2]. Therefore, novel targeted therapies, such as antibody-drug conjugates, are expected to further improve outcomes for mUC patients.

The antibody-drug conjugate enfortumab vedotin (EV), composed of human anti-nectin-4 monoclonal antibody and microtubule inhibitor monomethyl auristatin E (MMAE), is a promising treatment for mUC. A phase II EV-201 trial showed that EV therapy after platinum and anti-PD-1/PD-L1 therapies achieved overall and complete response (CR) rates of 44% and 12% [3]. Similarly, a phase III EV301 trial demonstrated superior survival outcomes compared to single-agent chemotherapy in mUC patients (median overall survival, 12.88 vs. 8.97 months) [4]. Thus, EV was approved in Japan as posttreatment for mUC patients resistant to platinum and anti-PD-1/PD-L1 therapies [5].

Renal impairment is a defining feature for many mUC patients, as seen in the EV-301 trial in which almost half of the patients had moderate or severe impairment [4]. However, patients with end-stage renal disease (ESRD) were excluded from EV-201 and EV-301 trials, leaving efficacy in hemodialysis patients unclear. Here, we report the case of a mUC patient, on hemodialysis for complete urinary tract extirpation, who was successfully treated with EV. The CARE Checklist has been completed by the authors for this case report and attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000530780).

Case Report

A 74-year-old, nonsmoking woman with a history of multiple bladder cancer (BCa) recurrences (treated with a transurethral resection of bladder tumor and intravesicular BCG therapy) was referred to us in March 2018 with a diagnosis of BCa and right upper urinary tract urothelial carcinoma. She underwent transurethral resection of bladder tumor and laparoscopic right radical nephroureterectomy, both revealing low-grade, non-muscle-invasive urothelial carcinoma. Four months later, multiple recurrences of BCa (pTa, low-grade) occurred and she underwent radical cystectomy with ileal conduit diversion. In July 2019, recurrences of left urinary tract urothelial carcinoma (pTa low-grade) led to left radical nephroureterectomy and ileal conduit resection with simultaneously initiated hemodialysis.

In May 2020, multiple pulmonary metastases appeared and were subsequently treated with gemcitabine-carboplatin followed by pembrolizumab. Unfortunately, follow-up computed tomography in March 2022 showed solid nodule progression in the lungs, including an 18 mm large nodule in the left upper lung field and a 12 mm large nodule in the right S6 field (Fig. 1).

Fig. 1.

Lung field findings as of March 2022 (a-1, 2), May 2022 at the end of the EV2 course (b-1, 2), and August 2022 after a drug withdrawal period (c-1, 2).

EV at 1.25 mg/kg (full dose) was administered on days 1, 8, and 15 of a 28-day cycle in April 2022 as third-line therapy with no dose adjustments. Although hemodialysis was scheduled approximately 24 h after EV infusion, her electrolytes remained stable throughout the treatment, precluding an emergency hemodialysis session. Adverse events were limited to grade 1 alopecia and dysgeusia. Follow-up computed tomography scans demonstrated CR after 2 EV courses (Fig. 1). She discontinued EV therapy after 3 cycles at her request and has remained in CR for over 4 months after EV therapy. The treatment timeline is summarized in Figure 2.

Fig. 2.

Timeline of treatment.

Discussion

As published data on EV efficacy and safety in mUC patients undergoing hemodialysis for ESRD is scarce, the present case demonstrates the clinical applicability and safety of EV for such patients. Antibody-drug conjugates have emerged as a selective delivery vector for cytotoxic agents into tumor tissues to combat various malignancies [6]. A similar drug to EV, brentuximab vedotin (BV), composed of CD30-directed antibody and MMAE, was initially approved in the USA for relapsing Hodgkin’s lymphoma or systemic anaplastic large cell lymphoma [7]. Pharmacokinetic studies of BV showed that MMAE is metabolized by CYP3A4 and partially excreted (∼28%) into the urine [8], suggesting that renal impairment affects MMAE exposure. Unfortunately, no data on such pharmacokinetics in mUC patients are currently published.

Zhao et al. [9] investigated BV pharmacokinetics in hepatic or renal impaired patients at doses of 1.2 mg/kg BV (average starting dose 1.8 mg/kg) to reduce adverse effects in case those impairments were factors. Mild or moderate renal impairment (creatinine clearance ≥30 and <80 mL/min) had no effect on MMAE exposure but severe renal impairment (creatinine clearance <30 mL/min) increased MMAE exposure approximately 1.9-fold. However, the rates of BV-related, serious adverse events did not significantly differ between renal impairment and unimpaired groups. Moreover, Nanni et al. [10] reported an ERSD case undergoing hemodialysis that was successfully treated with BV for systemic anaplastic large cell lymphoma with only grade 1 peripheral sensory neuropathy. These results suggest that, although MMAE exposure is increased, toxicity is not clinically significant for ERSD patients.

The EV-201 trial demonstrated efficacy and safety of EV for cisplatin-ineligible mUC patients in cohort 2, including the 69% of patients with moderate or severe impaired renal function (creatinine clearance ≥15 and <60 mL/min) [11]. In that trial, EV was administered at 1.25 mg/kg on days 1, 8, 15 of each 28-day cycle, without dose modifications. Objective response and Grade 3 or 4 treatment-related AEs rates were 52% and 55%. Similarly, grade 3 or higher treatment-related AEs in EV-201 (cohort 1) and EV-301 trials were 54% and 51% in patients who previously received platinum regimens [3, 4]. These results suggest that EV may be tolerable in mUC patients with renal impairment as the present case did not observe severe AEs at full EV dosing. Another report also detailed a comparable mUC case with peritoneal dialysis that achieved near CR after the standard EV dose [12] with only a grade 2 rash. These findings support EV as a promising therapy for ERSD patients with mUC.

We are the first to report CR by mUC after EV in an ESRD patient undergoing hemodialysis. Our case demonstrates the safety and efficacy of EV in this setting. However, individual safety and efficacy evaluations in this population require further pharmacokinetic and clinical studies. Currently, novel antibody-drug conjugates, such as sacituzumab govitecan [13] and disitamab vedotin [14], are in development and the number of treatment options is expected to increase. However, a lack of predictive power for these therapies relegates them to the same need for large, complex, and lengthy studies as other, similar drugs. If accurate prediction and progression tracking through biomarkers (e.g., genetic profiling of tumor DNA through liquid biopsy) can be fully developed over the next 5 years, these novel therapies will become an important suite of options in the treatment of mUC patients with ESRD.

Statement of Ethics

Written informed consent for publication of this case report and any accompanying images was obtained from the patient. Ethical approval is not required for this study in accordance with local or national guidelines.

Conflicts of Interest Statement

The authors have no conflicts of interest to disclose.

Funding Sources

No funding was received.

Author Contributions

B.I. was involved in patient care, reviewed the literature, collected patient data, and prepared the manuscript. M.S. prepared and revised the manuscript. S.K. revised the manuscript. Y.N., T.Y., A.I., T.K.a., T.K.i., H.N.e., and A.H. treated patients. B.J.M. performed English editing. H.N.i. was involved in the treatment of patient care and revised the manuscript. All authors read and approved the final manuscript.

Funding Statement

No funding was received.

Data Availability Statement

All data generated or analyzed in this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.