Astellas Pharma and Seagen announced positive topline results from the second cohort of patients in the pivotal phase 2 single-arm clinical trial known as EV-201. The cohort is evaluating the antibody-drug conjugate PADCEV? (enfortumab vedotin-ejfv) for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and have not received a platinum-containing chemotherapy and are ineligible for cisplatin. Results showed a 52 percent objective response rate (ORR) [95% Confidence Interval (CI): 40.8, 62.4] per blinded independent central review and a median duration of response of 10.9 months. The most frequently reported treatment-related adverse events Grade 3 or greater that occurred in more than 5 percent of patients were: neutropenia, rash, fatigue, increased lipase, diarrhea, decreased appetite, anemia and hyperglycemia. Data from cohort 2 of the trial will be submitted for presentation at an upcoming scientific congress and will be discussed with regulatory authorities.

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer. The U.S. Food and Drug Administration (FDA) granted accelerated approval to PADCEV in 2019 based on results from the first cohort in this trial, which included patients whose disease had progressed during or following platinum-based chemotherapy and a PD-1/L1 inhibitor.

"Advanced urothelial cancer in patients who have received immunotherapy and are ineligible for cisplatin is a particularly difficult disease to treat," said Arjun Balar, M.D., Associate Professor of Medicine, Director Genitourinary Medical Oncology Program, NYU Laura and Isaac Perlmutter Cancer Center, NYU Langone Health and an investigator for the trial. "Typically, these patients are frail, suffer from multiple comorbidities beyond their urothelial cancer and are not able to tolerate additional treatment beyond immunotherapy, leading many to discontinue therapy altogether."

"We are committed to developing new treatments for patients with hard-to-treat cancers, such as those with locally advanced or metastatic urothelial cancer that has progressed following treatment with a PD-1 or PD-L1 inhibitor and who are ineligible for cisplatin therapy," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas. "We look forward to discussing these data with regulatory authorities including the FDA."

Urothelial cancer is the most common type of bladder cancer (90 percent of cases), and can also be found in the urothelial cells that line the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra. Globally, approximately 580,000 people will be diagnosed with bladder cancer in 2020, and bladder cancer will be attributed to approximately 210,000 deaths worldwide.

The EV-201 trial (NCT03219333) is a single-arm, pivotal phase 2 clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (cohort 2). The trial enrolled 128 patients in cohort 1 and 91 patients in cohort 2 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.

PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA's Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer. Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis). PADCEV is co-developed by Astellas and Seagen.