Seattle Genetics and Astellas Announce Results from Phase 1 Trial of Investigational Agent Enfortumab Vedotin in Combination with Immune Therapy Pembrolizumab as First-Line Treatment for Advanced Bladder Cancer

San Francisco, CA ( -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., “Astellas”) and Seattle Genetics, Inc. announced initial results from the phase 1 clinical trial EV-103. 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. The study met outcome measures for safety and exhibited encouraging clinical activity for this platinum-free combination in a first-line setting. The data will be presented during an oral session at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain (Abstract #901O). Enfortumab vedotin is a first-in-class antibody drug conjugate (ADC) that targets Nectin-4, a protein present on almost all urothelial tumor cells and associated with cancer formation.1
“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,” said Dr. Christopher J. Hoimes, 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.”
Fifty-one percent of patients (23/45) had an adverse event greater than or equal to Grade 3. Among these events, an increase in lipase was the most frequent (13 percent; 6/45). Four patients (9 percent) 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 percent; 5/45), hyperglycemia (7 percent; 3/45) and peripheral neuropathy (4 percent; 2/45); these rates were similar to those observed with enfortumab vedotin monotherapy.2 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.

These 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 percent (32/45; 95% Confidence Interval (CI): 55.7, 83.6). The complete response (CR) rate was 13 percent (6/45). Fifty-eight percent (26/45) of patients had a partial response and 22 percent (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, M.D., 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, M.D., 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.

About the EV-103 Trial

EV-103 is an ongoing, multi-cohort, open-label, multicenter phase 1 trial of enfortumab vedotin alone or in combination, 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 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 in this analysis is safety. The analysis of these first cohorts 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.

Additional cohorts in the EV-103 study will evaluate enfortumab vedotin:
• with cisplatin or carboplatin in a first-line setting for metastatic disease 
• in combination with pembrolizumab and carboplatin or cisplatin in first-line metastatic disease 
• as a monotherapy or in combination with pembrolizumab in muscle invasive disease 
• with pembrolizumab in second-line metastatic disease; and
• with gemcitabine in first- or second-line metastatic disease.3

Clinical trial identification



1. Vlachostergios P, Jakubowski C, Niaz J, et al. (2018). Antibody-Drug Conjugates in Bladder Cancer. Bladder Cancer (Version 4.2018).
2. 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
3. A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103).

Source: Ezez. 2019. "Seattle Genetics and Astellas Announce Results from Phase 1 Trial of Investigational Agent Enfortumab Vedotin in Combination with Immune Therapy Pembrolizumab as First-Line Treatment for Advanced Bladder Cancer".
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