Abstract
Enfortumab vedotin recently demonstrated greater efficacy than standard chemotherapy in patients with previously treated advanced urothelial cancer: In a phase III trial, the agent led to a median overall survival of 12.9 months, compared with 9 months in patients who received chemotherapy.
Enfortumab vedotin (Seattle Genetics/Astellas Pharma) recently demonstrated greater efficacy than standard chemotherapy in patients with previously treated advanced urothelial cancer. In a phase III trial, patients treated with the agent had a median overall survival (OS) of 12.9 months, compared with 9 months in patients who received chemotherapy. The results were presented at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium, held virtually February 11–13, and simultaneously published (N Engl J Med 2021 Feb 12 [Epub ahead of print]).
“Enfortumab vedotin represents a major leap in moving forward with treating urothelial carcinoma,” says senior author Daniel Petrylak, MD, of Yale School of Medicine in New Haven, CT. He explains that previously patients with metastatic disease had few options after chemotherapy and immunotherapy.
Enfortumab vedotin is an antibody-drug conjugate (ADC) that combines the monoclonal antibody enfortumab with monomethyl auristatin E (MMAE), a drug that disrupts microtubule formation. Enfortumab targets Nectin-4, a cell-adhesion molecule overexpressed in more than 90% of metastatic urothelial cancers. After the cell imports the ADC, MMAE is cleaved off, arresting the cell cycle and leading to apoptosis. Enfortumab vedotin's performance in a phase Ib/II trial led to an accelerated FDA approval in 2018 as a third-line treatment.
The phase III EV-301 trial enrolled patients with locally advanced or metastatic urothelial carcinoma whose disease worsened after platinum-containing chemotherapy and anti–PD-1/PD-L1 therapy. In total, 301 patients received enfortumab vedotin and 307 received the investigator's choice of chemotherapy. Among the patients treated with enfortumab vedotin, 40.6% responded, compared with 17.9% of patients who received chemotherapy. In addition to longer OS, the enfortumab vedotin group also had a longer progression-free survival—5.6 months versus 3.7 months.
More than 90% of patients in both groups experienced side effects, and around half of the patients in each group experienced grade 3 or higher adverse events. Side effects from enfortumab vedotin included neuropathy, hyperglycemia, rash, and neutropenia.
“This is a clinically meaningful extension of overall survival for this patient population,” says Tian Zhang, MD, of Duke University School of Medicine in Durham, NC, who was not involved in the study. “Urothelial cancer tends to have multiple drivers of tumorigenesis, and not any one of our currently available treatments is able to control disease completely.” These results further support the approval of enfortumab vedotin, she adds.
“I think what we'll see is the expansion of life—people living longer as a result of the sequential application of these treatments,” says Arlene Siefker-Radtke, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was not connected to the work. “It was only in the past five years that we gained a second-line therapy with immunotherapy,” she adds, and now both second- and third-line strategies can extend survival by around a year for some patients. Siefker-Radke notes that enfortumab vedotin is being tested in combination with the PD-1 inhibitor pembrolizumab (Keytruda; Merck) as a first-line treatment for metastatic disease.
Patients with certain preexisting conditions such as liver disease or diabetes may have more serious adverse effects from enfortumab vedotin, Siefker-Radtke notes. In addition, it remains unclear why less than half of patients with advanced disease responded to the drug. “There are clearly mechanisms of resistance that likely impact patient outcomes,” Siefker-Radtke says.
However, enfortumab vedotin's ability to target urothelial cancer cells reduces the risk of systemic toxicity, Siefker-Radtke says, making it a good option for patients who cannot tolerate platinum-based chemotherapy after immunotherapy. “The strategy of using an antibody to get these very toxic agents directly to the tumor appears very promising.” –Conor Gearin
