Earlier this year, positive top-line results from the first cohort evaluating the investigational antibody-drug conjugates (ADC) enfortumab vedotin (also known as ASG-22CE) showed a positive, high tumor response.
The ongoing single-arm, pivotal phase II single-arm clinical trial known as EV-201 (NCT03219333) studied the drug patients with locally advanced or metastatic urothelial cancer who had received previous treatment with both platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.
Advances in treatment
Despite recent advances in treatment, approximately 80% of people do not respond to PD-1 or PD-L1 inhibitors, which are the standard of care after platinum-containing therapy has failed as an initial treatment for advanced disease. These patients have few treatment options.
“There remains a high unmet need for effective treatments upon progression after initial chemotherapy and immunotherapy,” noted Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.
“After progression on platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor, patients with locally advanced or metastatic urothelial cancer are left with no approved standard of care treatment options,” added Steven Benner, M.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development at Astellas.
The researchers involved in this clinical trial tried to confirm if enfortumab vedotin is one of the potential drug candidates able to fill this need.
“These data are very encouraging, and we look forward to discussing the data with relevant health authorities,” Benner added.
In this trial, a total of 128 patients were enrolled at multiple centers internationally. The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability
Enfortumab vedotin is an investigational antibody-drug conjugate. These novel agents 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. Enfortumab vedotin is composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent Monomethyl Auristatin E or MMAE, using a proprietary linker technology developped by Seattle Genetics.
The trial drug targets Nectin-4, a cell adhesion molecule identified as an ADC target by Astellas, which is expressed on many solid tumors.
Results showed a high objective response rate (ORR) per blinded independent central review. The duration of response was consistent with that recently reported in the previous phase I study (EV-101; NCT02091999) [A]
Updated trial results
Updated results presented today during the annual meeting of the American Society of Clinical Oncology (ASCO), being held May 31 – June 4, 2019 in Chicago, Ill, demonstrated that enfortumab vedotin rapidly shrank tumors in most patients, resulting in an objective response rate (ORR) of 44% (55/125; 95% Confidence Interval (CI): 35.1-53.2). Complete responses (CR) were also observed in 12% of patients (15/125). The median duration of tumor response was 7.6 months (range 0.95-11.3+).
This cohort was open to patients with locally advanced or metastatic urothelial cancer who had received previous treatment with a platinum-containing chemotherapy and a PD-1/L1 checkpoint inhibitor.
Responses were similar in the subgroups of patients analyzed, including those who had the worst prognosis, such as patients who had three or more previous lines of therapy, patients with liver metastases, and those who had not responded to a PD-1/L1 inhibitor.
The most common treatment-related adverse events reported by 40% or more patients included fatigue, alopecia, decreased appetite, taste distortion rash and peripheral neuropathy.
Enfortumab vedotin is an investigational antibody-drug conjugate (ADC) that targets Nectin-4, a therapeutic target that is highly expressed in multiple solid tumors including urothelial cancers. Based on preliminary results from a phase 1 trial (EV-101), enfortumab vedotin was granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for patients with locally advanced or metastatic urothelial cancer whose disease has progressed during or following treatment with a PD-1 or PD-L1 inhibitor.
Urothelial cancer is the most common type of bladder cancer (90% of all 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.  Approximately 80% of people do not respond to PD-1 or PD-L1 inhibitors after a platinum-containing therapy has failed as an initial treatment for advanced disease.  There are currently no approved therapies for metastatic urothelial cancer once it has progressed after chemotherapy and a PD-1 or PD-L1 inhibitor. 
“Outcomes for patients diagnosed with locally advanced or metastatic urothelial cancer are generally poor, and treatment options after initial chemotherapy and immunotherapy are very limited,” said Daniel P. Petrylak, M.D., Professor of Medicine and of Urology, Yale Cancer Center, New Haven.
“These data have the potential to change the treatment course of advanced urothelial cancer, and it is gratifying to see these results for patients.”
In March 2018, the U.S. Food and Drug Administration (FDA) granted enfortumab vedotin a breakthrough therapy designation for people with locally advanced or metastatic urothelial cancer that has progressed during or following checkpoint inhibitor therapy.
Seattle Genetics and Astellas plan to submit a Biologics License Application (BLA) to the FDA later this year based on the results from the EV-201 trial. A global, randomized phase III clinical trial (EV-301) is ongoing and intended to support global registration as well as to serve as the confirmatory randomized trial for enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor.
In addition to the ongoing confirmatory phase III study intended to also support global registration, development of enfortumab vedotin is underway in earlier lines of treatment for locally advanced or metastatic urothelial cancer, including in newly diagnosed patients in combination with pembrolizumab and/or platinum chemotherapy.
The EV-201 phase II trial continues to enroll patients in who have not received a platinum-containing chemotherapy and who are ineligible for cisplatin.
Commenting on the study and the study results of the phase II EV-201 trial, Robert Dreicer, MD, MS, MACP, FASCO, deputy director of University of Virginia Cancer Center, who serves as the director of solid tumor oncology within the division of hematology/oncology and is a professor of medicine and urology and ASCO expert noted: “If advanced urothelial cancer progresses following treatment with platinum-based chemotherapy and immunotherapy with checkpoint inhibitors there are no FDA approved treatment options. Although this is a small, phase II trial, the anti-tumor activity demonstrated in patients whose disease progressed on chemotherapy and immunotherapy is promising, we await larger studies to confirm these early findings.”
[A] A Study of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4 (EV-101)- NCT02091999
[B] A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (EV-201) – NCT03219333
[C] A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301) – NCT03474107
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