The FDA has granted regular approval to enfortumab vedotin-ejfv (Padcev®, Astellas Pharma US, Inc.) for patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy or those who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
"Patients with locally advanced or metastatic urothelial carcinoma have poor survival following progression after platinum-containing chemotherapy and PD-1/PD-L1 inhibitor regimens," wrote Thomas Powles, MBBS, MRCP, MD, Director of the Barts Cancer Centre in London, UK, and colleagues, in the abstract for the phase 3 EV-301 study (NCT03474107), on which the approval was based. "Enfortumab vedotin is an antibody-drug conjugate directed to Nectin-4, a cell adhesion molecule highly expressed in urothelial carcinoma, with remarkable efficacy observed in a single-arm trial in this setting."
In December 2019 the FDA granted accelerated approval to enfortumab vedotin-ejfv for patients with locally advanced or metastatic urothelial cancer who had received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. The open-label, randomized, multicenter trial that was meant to confirm the clinical benefit of the 2019 accelerated approval, enrolled 608 patients. Patients were randomized 1:1 to receive either enfortumab vedotin-ejfv 1.25 mg/kg on Days 1, 8, and 15 of a 28-day cycle or investigator's choice of single-agent chemotherapy, which could be docetaxel, paclitaxel, or vinflunine. The primary efficacy end point was overall survival; secondary end points were progression-free survival, objective response rate, and disease control rate per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
The median overall survival was 12.9 months for patients who received enfortumab vedotin-ejfv versus 9.0 months in the single-agent chemotherapy arm. Median progression-free survival in the enfortumab vedotin-ejfv arm was 5.6 months compared with 3.7 months in the single-agent chemotherapy arm. The overall response for patients receiving enfortumab vedotin-ejfv was 40.6% versus 17.9% in the group of patients receiving single-agent chemotherapy. The disease control rate in the enfortumab vedotin-ejfv arm was 71.9%, compared with 53.4% of patients receiving single-agent chemotherapy.
Patients who were ineligible for cisplatin-containing chemotherapy were evaluated in Cohort 2 of EV-201 (NCT03219333), a single-arm, multi-cohort, international trial. This clinical trial enrolled 89 patients with locally advanced or metastatic urothelial cancer who received a prior PD-1 or PD-L1 inhibitor and were ineligible for cisplatin-containing chemotherapy. The primary efficacy end point was confirmed overall response rate, and the key secondary efficacy end point was response duration. The confirmed overall response rate was 51%, the complete response rate was 22%, and the median response duration was 13.8 months.
The most common adverse reactions and laboratory abnormalities occurring in at least 20% of patients were rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased, and dry skin. Serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can also occur.
"Enfortumab vedotin is the first therapy to show significant survival advantage over standard chemotherapy in patients with treatment-experienced locally advanced or metastatic urothelial carcinoma," concluded Dr. Powles and colleagues in their March 2021 meeting abstract published in the Journal of Clinical Oncology. "With robust clinical benefit and a tolerable safety profile, enfortumab vedotin is a new standard of care for this aggressive disease."
The recommended dose of enfortumab vedotin-ejfv is 1.25 mg/kg, up to a maximum dose of 125 mg, administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of a 28-day cycle until disease progression or unacceptable toxicity.
For More Information
Powles T, Rosenberg JE, Sonpavde G, et al (2021). Primary results of EV-301: a phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol, 39(suppl_6). Abstract 393. DOI:10.1200/JCO.2021.39.6_suppl.393
Balar AV, McGregor BA, Rosenberg JE, et al (2021). EV-201 Cohort 2: enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol, 39(suppl_6). Abstract 394. DOI:10.1200/JCO.2021.39.6.suppl.394
Clinicaltrials.gov (2021). A study to evaluate enfortumab vedotin versus (vs) chemotherapy in subjects with previously treated locally advanced or metastatic urothelial cancer (EV-301). NLM identifier: NCT03474107.
US Food & Drug Administration (2021). FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-regular-approval-enfortumab-vedotin-ejfv-locally-advanced-or-metastatic-urothelial-cancer
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