Treatment with enfortumab vedotin generated robust responses in patients with locally advanced or metastatic urothelial carcinoma. In a phase II trial of 125 patients who had previously received platinum-based chemotherapy and a PD-1 or PD-L1 checkpoint inhibitor, the overall response rate was 44%. Although nearly all patients experienced a treatment-related adverse event, most side effects were mild to moderate.

Building on data released in 2017, researchers recently reported robust responses in a phase II trial of enfortumab vedotin (Seattle Genetics/Astellas Pharma) in patients with urothelial cancer who had already received multiple treatments. Study findings, which included a confirmed overall response rate of 44%, were also presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL.

Patients diagnosed with locally advanced or metastatic urothelial cancer typically begin treatment with platinum-based chemotherapy, shifting to one of five approved checkpoint inhibitors if their disease worsens. However, about 80% of people who receive these immunotherapies eventually stop responding, and no other treatments are specifically approved for the disease. “There's a high unmet medical need,” said Daniel Petrylak, MD, of Yale Cancer Center in New Haven, CT, who co-led the trial with Jonathan Rosenberg, MD, of Memorial Sloan Kettering Cancer Center in New York, NY.

An antibody–drug conjugate (ADC), enfortumab vedotin consists of a monoclonal antibody connected to the microtubule-disrupting agent monomethyl auristatin E (MMAE) with a protease-cleavable linker. The antibody targets the cellular adhesion molecule Nectin-4, which is highly expressed in several solid tumors—and nearly all urothelial carcinomas—binding with high affinity. Tumor cells internalize the complex, triggering the release of MMAE. This action disrupts microtubule formation, leading to cell-cycle arrest and apoptosis.

Researchers reported the results of Cohort 1 of EV-201, a single-arm trial that included 125 patients previously treated with platinum-based chemotherapy and a PD-1 or PD-L1 checkpoint inhibitor. (Cohort 2 continues to enroll patients previously treated only with a checkpoint inhibitor.) Fifty-five patients (44%) responded to the ADC, with 15 (12%) experiencing a complete response; another 35 (28%) had stable disease. The median duration of response was 7.6 months, and responses were observed across all subgroups and regardless of reaction to earlier anti–PD-1/PD-L1 antibody, said Petrylak, who presented the findings at the ASCO meeting.

Additionally, patients had an estimated median progression-free survival of 5.8 months and an estimated median overall survival of 11.7 months.

Because skin expresses Nectin-4, 48% of patients developed rashes due to the off-target effect of the drug, although they were generally mild and manageable with corticosteroids, antihistamines, or a reduced dose of enfortumab vedotin. ADCs containing MMAE have been associated with peripheral neuropathy, and 50% of patients did develop it. However, the side effect was grade 3 or worse in just 3% of patients. Overall, Petrylak said, the drug was well tolerated.

“If approved,” Petrylak said, “enfortumab vedotin may have the potential to become a new standard of care in patients who have progressed after platinum-based chemotherapy and PD-1/PD-L1 inhibitors.” The FDA granted breakthrough therapy designation to the drug in 2018 based on the results of the phase I trial.

Andrea Necchi, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, who discussed the research at the ASCO meeting, called the data “very promising.”

However, he wondered whether any benefit attributed to enfortumab vedotin might be a delayed effect of the prior immunotherapy. He suggested that researchers tease out the amount of time that elapsed between the end of checkpoint inhibitor therapy and the start of treatment with enfortumab vedotin.

In addition, Necchi stressed the need for biomarkers to determine those most likely to respond. “What we need is a prediction tool to be able to fine-tune counseling patients and inform therapeutic strategies.” –Suzanne Rose