ASCO GU 2021: 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

(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. Patients who are ineligible for cisplatin and progress on immune checkpoint blockade have limited treatment options, and many efforts are underway to expand the therapeutic armamentarium for this disease context.

Enfortumab vedotin is an antibody-drug conjugate therapeutic with promising efficacy in locally advanced or metastatic urothelial carcinoma. It consists of an antibody against Nectin-4, a protein highly expressed on the surface of most urothelial carcinoma. This antibody is conjugated to the anti-microtubule agent Monomethyl auristatin E. Once the antibody binds the Nectin-4 expressing cell, the agent is internalized, and the chemotherapy agent is released to cause eventual cell death, as illustrated below. 


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Enfortumab vedotin provides a survival benefit for patients with advanced urothelial carcinoma who have progressed on cisplatin and immune checkpoint blockade. In this presentation, Dr. Balar presented results from Cohort 2 of the phase 2 EV-201 study, evaluating enfortumab after immunotherapy in cisplatin-ineligible patients.  The study schema is described below. 

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Patients eligible for the study were those with locally advanced unresectable or metastatic urothelial carcinoma that were previously treated with a PD-1 or PD-L1 inhibitor, were deemed to be ineligible for cisplatinum, had not received any prior platinum agent, and were progressing since most recent therapy. Patients were ineligible if they had Grade 2 or worse ongoing sensory or motor neuropathy, active CNS metastases, or uncontrolled diabetes.

In total, 91 patients were enrolled and 89 patients were treated. At the time of data cutoff, 73 patients had discontinued therapy, the majority due to progressive disease. Sixteen patients remained on treatment at the time of analysis with the longest time of treatment of 24.6 months, and 44 patients had died. The median time on treatment was 6 months. Patient demographics are summarized below, and are notable for a somewhat older patient population than other trials in this setting, likely related to older patients more commonly being ineligible for platinum therapy.

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Blinded independent review results are shown below. The response rate was 52%, with 20% of patients experiencing a complete response as their best overall response. 88% of assessable patients experienced some reduction in their tumor volume. 

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Responses were noted in all subgroups, including upper tract patients, those with liver metastases, and those who did not respond to prior immune checkpoint blockade. 

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The median time to response was 1.81 months and the median duration of response was 10.9 months (95% CI 5.78-not reached). The median progression free survival was 5.8 months (95% CI 5.03-8.28), and the median overall survival was 14.7 months (95% CI 10.51-18.20). 

Treatment related adverse events led to discontinuation of therapy in 16% of patients, most commonly due to peripheral neuropathy. There were four treatment related deaths, 1 each from pneumonitis, acute kidney injury, metabolic acidosis and multiple organ dysfunction syndrome. Three of these deaths occurred within 30 days of treatment and were in patients with BMI greater than 30. Regarding adverse events of specific interest, 61% of patients had skin reaction of any grade, 17% were grade 3 or higher. These started a median of 0.5 months after treatment initiation, and 80% had improvement in this side effect. 54% of patients experienced any peripheral neuropathy, 8% were grade 3 or worse, and this began a median of 2.4 months after treatment onset. 

Dr. Balar concluded that the 52% ORR and 20% CR rate represent the highest numerical response rates of any therapy trialed to date in this patient population (cisplatin ineligible, progressed on immune checkpoint blockade. When balanced with safety data, these results support the use of enfortumab vedotin in this clinical context for advanced urothelial carcinoma.  

Presented by: Arjun V. Balar, MD, Perlmutter Cancer Center, NYU Langone Health, New York, NY

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021

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