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Enfortumab Vedotin in Urothelial Carcinoma

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Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy.

BACKGROUND Patients with advanced urothelial carcinoma have poor overall survival after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment.

The United States Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin (Padcev®, manufactured and marketed by Astellas Pharma US, Inc., Northbrook, Illinois 60062; distributed and marketed by Seattle Genetics, Inc., Bothell, WA 98021) on December 18, 2019, for patients with locally advanced or metastatic urothelial cancer who have previously received platinum chemotherapy and a PD-L1 inhibitor.

Enfortumab Vedotin (EV) is a novel antibody-drug conjugate targeting Nectin-4, which is overexpressed in urothelial cancer. A recent study published by Takahashi et al. in Investigational New Drugs studied EV in locally advanced/metastatic urothelial cancer in a phase I study (NCT03070990).1

PURPOSE: Locally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti–programmed death 1 or anti–programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody–drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma.
Conference Coverage
Conference Highlights Written by Physician-Scientist
Presented by Christopher Hoimes, DO, Ph.D.
(UroToday.com) The standard of care for patients with muscle-invasive bladder cancer remains neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and pelvic lymph node dissection (RC+PLND). However, many patients will experience disease recurrence, progression, and bladder cancer-related death following neoadjuvant chemotherapy and RC+PLND. This has led to interest in both adjuvant therapy and improved neoadjuvant therapies.
Presented by Ronac Mamtani, MD
(UroToday.com) In EV-301, a randomized, open-label phase 3 study, enfortumab vedotin, a Nectin-4–directed therapy, significantly prolonged median overall survival by ̃3.9 months and reduced the risk of death by 30% compared with standard chemotherapy (docetaxel, paclitaxel, or vinflunine) in patients with previously treated locally advanced/metastatic urothelial carcinoma.1 
Presented by Terence W. Friedlander, MD
(UroToday.com) Significant unmet need remains for people with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma. In the first-line setting, carboplatin-based regimens have demonstrated poor tolerability, modest objective response rate, and limited durability. PD-1/PD-L1 inhibitors demonstrate durable responses, however, only a minority of patients achieve a response (ORR 24-29%). Enfortumab vedotin is an antibody-drug conjugate delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE) to targeted tumor cells expressing Nectin-4.
Presented by Bradley A. McGregor, MD
(UroToday.com) Approximately half of the patients with advanced urothelial carcinoma in the United States are cisplatin-ineligible. Of note, cisplatin-ineligible, platinum-naive patients with locally advanced or metastatic urothelial carcinoma who progress on or after anti-PD-1/L1 treatment have a poor prognosis and few treatment options. Enfortumab vedotin, a Nectin-4-directed antibody-drug conjugate, demonstrated an overall survival benefit in patients with locally advanced or metastatic urothelial carcinoma who previously received anti-PD-1/L1 treatment and platinum-containing chemotherapy in EV-3011.
Presented by Arlene O. Siefker-Radtke, MD
In this presentation, Arlene O. Siefker-Radtke, MD provided a discussion on two presentations on Enfortumab Vedotin (EV)  in previously treated urothelial cancer. Primary results of EV-301 and EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors.
Presented by Arjun Balar, MD
(UroToday.com) Cisplatin-based chemotherapy is the standard of care in first-line for metastatic urothelial carcinoma and is associated with an overall survival benefit. However, approximately half of patients with locally advanced or metastatic urothelial carcinoma in the US are cisplatin-ineligible. Cisplatin-ineligible, platinum-naive patients with locally advanced or metastatic urothelial carcinoma who progress on or after PD-1/L1 inhibitors have a poor prognosis and few treatment options. 
Presented by Thomas Powles, MBBS, MRCP, MD
(UroToday.com) Platinum-based chemotherapy, sequenced with programmed cell death protein-1/programmed death-ligand 1 (PD-1/L1) inhibitors, is the standard of care for patients with advanced urothelial carcinoma. Platinum-based chemotherapy used in the first-line is associated with response rates of 36-64%, but intrinsic and acquired resistance occurs. PD-1/L1 inhibitors are used in the first-line, first-line maintenance, and in platinum-refractory disease, with durable responses, but only in a minority of patients.
Presented by Carissa Chu, MD
(UroToday.com) Enfortumab vedotin is an antibody-drug conjugate targeting Nectin-4 (encoded by the PVRL4/NECTIN4 gene) approved for treatment-refractory metastatic urothelial cancer based on several studies.1-3 EV-201 represented a heavily pre-treated population with a 44% overall response rate, 12% complete response rate, 7.6-month median duration of response, 11.7-month median overall survival, and 5.8-month progression-free survival.2 
Presented by Arlene O. Siefker-Radtke, MD
(UroToday.com) The ASCO GU 2021 Genitourinary Cancers Symposium annual meeting included an invited discussion from Dr. Arlene Siefker-Radtke discussing “Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma” and “EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors.”
Presented by Arjun V. Balar, MD
(UroToday.com) Cisplatin chemotherapy is the standard of care for medically fit patients in advanced urothelial carcinoma. Unfortunately, up to 50% of these patients are medically ineligible for cisplatin due to low-performance status, renal dysfunction, or other medical comorbidities.  Immune checkpoint blockade is a first-line therapeutic option in either platinum ineligible patients or carboplatin eligible patients whose tumors also express PD-L1. 
Presented by Michiel S. van der Heijden, MD, PhD
Platinum-based chemotherapy is the mainstay of first-line treatment for medically eligible patients with advanced urothelial carcinoma (UC). Unfortunately, up to 50% of patients are unable to receive cisplatin, and disease progression often develops even for patients who receive cisplatin.
Presented by Peter O'Donnell, MD
It is well-known that locally advanced and metastatic urothelial carcinoma is an incurable disease with poor overall survival (OS), especially in patients who progress on or after platinum-containing chemotherapy.
Presented by Nataliya Mar, MD
(UroToday.com) Treatment with platinum-based chemotherapy and program death ligand 1 (PD-L1) immune checkpoint inhibitor has been shown to have a modest objective response rate (ORR) and limited durability, emphasizing the critical unmet need in the first-line setting for patients with locally advanced or metastatic urothelial carcinoma.1
Presented by Jonathan E. Rosenberg, MD
(UroToday.com) The prognosis for patients with locally advanced and metastatic urothelial carcinoma of the bladder is poor. Currently, cisplatin-based chemotherapy is the standard of care for these patients. Immunotherapeutic approaches (utilizing atezolizumab and pembrolizumab) are currently approved as first-line therapy in patients who are ineligible for cisplatin-containing regimes and have PD-L1 expression and those who are ineligible for platinum-containing regimes regardless of PD-L1 status. In the second line setting, a number of other agents are also approved.
Presented by Jonathan E. Rosenberg, MD
San Francisco, California (UroToday.com)  Patients with metastatic urothelial cancer traditionally, have faced limited options. While platinum chemotherapy is the standard in the first line setting, many patients are ineligible. Previously, it has been shown that PD-1/PD-L1 inhibitors, demonstrate promising effectiness in this setting. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent MMAE to cells expressing Nectin-4. This receptor is highly expressed in urothelial cells and in previous studies, EV has shown activity in previously treated metastatic patients.
Presented by Jonathan Rosenberg MD
San Francisco, California (UroToday.com) Standard of care first-line approaches for the treatment of locally advanced and metastatic urothelial carcinoma include cisplatin. Unfortunately, this therapy is often toxic with overall response rates of 50% or less. Additionally, a significant proportion of patients are deemed medically unable to receive cisplatin therapy, and options for these patients are even more limited. 
Presented by Christopher J. Hoimes, DO
Barcelona, Spain (UroToday.com) Recently, we’ve seen some major advances for patients with locally advanced and metastatic urothelial carcinoma.  For instance, pembrolizumab, an anti-PD-1 antibody has received regulatory approval for both cisplatin ineligible patients in the first-line setting and also in the post-platinum treated population.1, 2 
Presented by Yohann Loriot, MD, Ph.D.
Barcelona, Spain (UroToday.com) Treatment options for advanced urothelial cancers (UC) are limited, and the development of more effective therapies is a clear unmet need. In this session, Dr. Loriot discussed the previous two presentations: EV-103 looking at the combination of enfortumab vedotin (EV) and pembrolizumab as first line therapy in locally advanced and metastatic UCs, and BISCAY looking at targeted therapies based on tumor genomics in combination with standard of care durvalumab in platinum-refractory UC patients.
Presented by Christopher J. Hoimes, DO
Barcelona, Spain (UroToday.com)  Enfortumab vedotin is an antibody-drug conjugate comprised of the nectin-4 antibody enfortumab coupled to the microtubule
Presented by Christopher J. Hoimes, DO
Barcelona, Spain (UroToday.com) Platinum-based chemotherapy is the standard of care in patients with locally advanced or metastatic urothelial carcinoma, but this therapy is often toxic with overall response rates of 50% or less. These tumors highly and consistently express the type I transmembrane cellular adhesion protein, Nectin-4.
Presented by Christopher J. Hoimes, DO
Barcelona, Spain (UroToday.com) Platinum-based chemotherapy remains the standard of care for patients with locally advanced or metastatic urothelial carcinoma. Despite the use of first-line PD-1/PD-1L inhibitors, 71–76% of patients who are cisplatin-ineligible do not respond to treatment.
Presented by Daniel Peter Petrylak, MD
Chicago, IL (UroToday.com) After cisplatin-based chemotherapy and immune checkpoint inhibitors, there exist a paucity of effective therapies for patients with metastatic urothelial carcinoma (mUC). Enfortumab vedotin (EV) is an antibody-drug
Presented by Daniel P. Petrylak, MD
Chicago, IL (UroToday.com) Locally advanced or metastatic urothelial cancer remains a lethal disease with limited treatment options for patients who progress on or after platinum and/or checkpoint inhibitor therapy. Response rates to second-line PD-1/L1 inhibitors are 13-21%, with few options once patients progress. Furthermore, single-agent chemotherapy post-platinum and post-PD-1/L1 inhibitors show very limited activity (ORR 11%).1 
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