Initial results from EV-103, a phase I clinical trial (NCT03288545) of the investigational antibody-drug conjugate enfortumab vedotin (also known as AGS-22ME; Seattle Genetics/Astellas)* in combination with immune therapy pembrolizumab (Keytruda®; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.) as a first-line treatment for advanced urothelial (bladder) cancer, shows that study met outcomes measures for safety and exhibited encouraging clinical activity for this platinum-free combination in a first-line setting.
The findings presented during an oral session at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain, also confirmed that 71% of participating patients with locally advanced or metastatic urothelial cancer had a confirmed response.
Forty-five patients were evaluated for safety with the combination of the investigational agent enfortumab vedotin and the immune therapy pembrolizumab in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for treatment with cisplatin-based chemotherapy.
EV-103 is an ongoing, multi-cohort, open-label, multicenter phase I trial of enfortumab vedotin alone or in combination with a different drug, evaluating safety, tolerability and efficacy in muscle invasive, locally advanced and first- and second-line metastatic urothelial cancer.
The dose escalation-cohort and expansion cohort A of the study include locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. Patients were dosed in a 21-day cycle, receiving an intravenous (IV) infusion of enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At the time of this initial analysis, 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion cohort A) with locally advanced and/or metastatic urothelial cancer had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.
The primary outcome measure of the cohorts included safety. The analysis of these first cohorts also included several of the study’s secondary objectives. Key secondary objectives related to efficacy include objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and overall survival (OS). DOR and OS were not mature at the time of analysis and will be included in a future analysis.
More treatment options
Enfortumab vedotin is a first-in-class antibody-drug conjugate designed to target Nectin-4, a protein present on almost all urothelial tumor cells and associated with cancer formation.
Antibody-drug Conjugates such as enfortumab vedotin are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
To date, with five approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
“Advanced urothelial cancer is an aggressive disease for which more options are needed, especially for patients who are ineligible for first-line treatment with cisplatin,” noted Christopher J. Hoimes, DO, Director, Genitourinary Oncology, Case Comprehensive Cancer Center at University Hospitals Seidman Cancer Center, Cleveland, Ohio.
“This study tests the combination of the investigational agent enfortumab vedotin with the PD-1 inhibitor pembrolizumab, in a biomarker unselected population. Initial results provide support for further development of enfortumab vedotin combinations in this and other settings of urothelial cancer,” Hoimes added.
Fifty-one percent of patients (23/45) had an adverse event greater than or equal to Grade . Among these events, an increase in lipase was the most frequent (13%; 6/45). Four patients (9%) discontinued treatment due to treatment-related adverse events, most commonly peripheral sensory neuropathy. There was one death deemed to be treatment-related by the investigator attributed to multiple organ dysfunction syndrome.
Treatment-related adverse events of clinical interest that were greater than or equal to Grade 3 were rash (11%; 5/45), hyperglycemia (7%; 3/45) and peripheral neuropathy (4%; 2/45); these rates were similar to those observed with enfortumab vedotin monotherapy. Eleven percent (5/45) of patients had treatment-related immune-mediated adverse events of clinical interest greater than or equal to Grade 3 that required the use of systemic steroids (one event each of pneumonitis, dermatitis bullous, hyperglycemia, tubulointerstitial nephritis, myasthenia gravis). None of the adverse events of clinical interest were Grade 5 events.
The data demonstrated the combination of enfortumab vedotin plus pembrolizumab shrank tumors in the majority of patients, resulting in a confirmed objective response rate (ORR) of 71% (32/45; 95% Confidence Interval (CI): 55.7, 83.6). The complete response (CR) rate was 13%(6/45). Fifty-eight percent (26/45) of patients had a partial response and 22% (10/45) had stable disease. Ninety-one percent of responses were observed at the first assessment.
“These data are encouraging and support further exploration of a potential platinum-free combination of pembrolizumab and the investigational agent enfortumab vedotin,” said Roger Dansey, MD, Chief Medical Officer at Seattle Genetics.
“We are motivated by these results, and we will continue to study enfortumab vedotin alone and in combination with other agents in different stages of urothelial cancer,” said Andrew Krivoshik, MD, Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.
Enfortumab vedotin is currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1/L1 inhibitor and who have received a platinum-containing chemotherapy in a neoadjuvant/adjuvant, locally advanced or metastatic setting.
Additional cohorts in the EV-103 study will also evaluate enfortumab vedotin with cisplatin or carboplatin in a first-line setting for metastatic disease and in combination with pembrolizumab and carboplatin or cisplatin in first-line metastatic disease. Enfortumab vedotin will further investigated as a monotherapy or in combination with pembrolizumab in muscle invasive disease and with pembrolizumab in second-line metastatic disease and with gemcitabine in first- or second-line metastatic disease.
Urothelial cancer is the most common type of bladder cancer (90% all of cases). In 2018, more than 82,000 people were diagnosed with bladder cancer in the United States. Globally, approximately 549,000 people were diagnosed with bladder cancer last year, and there were approximately 200,000 deaths worldwide. 
The recommended first-line treatment for patients with advanced urothelial cancer is a cisplatin-based chemotherapy. For patients who are ineligible for cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens.
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 Rosenberg J. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019; DOI: 10.1200/JCO.19.01140
 A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103). Clinical trial: NCT03288545 Online. Last accessed September 27, 2019.
 American Society of Clinical Oncology. Bladder Cancer: Introduction (05-2019). https://www.cancer.net/cancer-types/bladder-cancer/introduction
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 National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 4; July 10, 2019. Online. Last accessed September 27, 2019.