Enfortumab Vedotin Shows Durable Responses in Pivotal Phase 2 Study of Advanced Urothelial Cancer

The antibody-drug conjugate (ADC) enfortumab vedotin-ejfv (Padcev) induced durable responses as treatment of patients with locally advanced or metastatic urothelial cancer (mUC) who have previously received immunotherapy but not a prior platinum-containing chemotherapy and are not eligible for cisplatin, according to the topline results from a second cohort of patients in a pivotal phase 2 study (NCT03219333), which were announced in a press release from Seagen Inc. and Astellas Pharma, Inc.

“Advanced urothelial cancer in patients who have received immunotherapy and are ineligible for cisplatin is a particularly difficult disease to treat,” said study investigator Arjun Balar, MD, associate professor of Medicine, Director Genitourinary Medical Oncology Program, NYU Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, in a statement. “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.”

The objective response rate (ORR) by blinded independent central review, which was the primary end point of the study, was 52% (95% CI, 40.8-62.4), and the median duration of response was 10.9 months with enfortumab vedotin.

“This is the first trial to report objective responses in patients with advanced urothelial cancer who had previously received immunotherapy but were ineligible for cisplatin in this setting due to inadequate kidney function or other conditions,” stated Roger Dansey, MD, chief medical officer at Seagen. “These promising new data from EV-201 may support a regulatory application to extend use of PADCEV in U.S. patients whose cancer has progressed after immunotherapy and who are ineligible for cisplatin.”

The most commonly treatment-related adverse events (AEs) of grade 3 or greater in severity, occurring in 5% or more of patients, included neutropenia, rash, fatigue, increased lipase, diarrhea, decreased appetite, anemia, and hyperglycemia.

The agent is a first-in-class ADC directed against Nectin-4, which is a protein on the surface of cells and highly expressed in bladder cancer. The FDA previously granted an accelerated approval to this agent in 2019 for the treatment

The full data from this cohort will be submitted for presentation at an upcoming medical meeting, and the companies will also have discussions with regulatory authorities.

Secondary end points in the study included duration of response (DOR), disease control rate at 16 weeks, progression-free survival (PFS), ORR by investigator assessment, DOR by investigator assessment, PFS by investigator assessment, overall survival, incidence of AEs, and incidence of laboratory abnormalities, as well as select pharmacokinetics parameters.

To be included in the study, patients had to have metastatic or locally advanced disease that is not resectable, have received prior treatment with an immunotherapy in the locally advances or mUC setting, and be platinum-naïve or ineligible for cisplatin at the time of enrollment. Patients must also have had progression or recurrence of disease following or during their most recent therapy, tumor tissue samples available for submission prior to study treatment, measurable disease, an ECOG performance status of ≤2, and a life expectancy of ≥3.

Patients were excluded from the study if they had ongoing sensory or motor neuropathy of ≥2; active central nervous system metastases; immunotherapy related to myocarditis, colitis, uveitis, or pneumonitis; prior enrollment to a clinical trial of enfortumab vedotin; or uncontrolled tumor-related pain/impending spinal cord compression.

“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, MD, PhD, senior vice president and oncology therapeutic area head, Astellas, in a statement. “We look forward to discussing these data with regulatory authorities including the FDA.”

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_{Seagen and Astellas announce positive topline results from second cohort of patients in phase 2 pivotal trial of padcev (enfortumab vedotin-ejfv) in advanced urothelial cancer. News Release. October 12, 2020. Accessed October 12, 2020. https://bit.ly/3dkfwBY}