FDA Approves Novel Drug Enfortumab Vedotin for Urothelial Cancer

Nick Mulcahy

December 19, 2019

The US Food and Drug Administration has granted accelerated approval to the novel agent enfortumab vedotin (PADCEV, Astellas) for the treatment of locally advanced or metastatic urothelial cancer that has progressed on chemotherapy and immunotherapy.

Eligible patients will have previously received immunotherapy with a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and with a platinum-containing chemotherapy, both of which are standard treatments for urothelial cancer. This accounts for more than 90% of bladder cancers, according to the FDA.

The new drug, which is delivered intravenously, is an antibody drug conjugate. It is a first-in-class agent directed against cell adhesion molecule Nectin-4, which is located on the surface of cells and highly expressed in bladder cancer. The antibody directs the product to these cells, and then releases the cytoxic monomethyl auristantin E.

"Antibody-drug conjugates are strategic tools in the targeted treatment of cancer. These conjugates combine the ability of monoclonal antibodies to target specific receptors on cancer cells and then deliver a drug to the cancer cell," said Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the agency's Center for Drug Evaluation and Research, in a statement.

"Metastatic urothelial cancer is an aggressive and devastating disease with limited treatment options, and the approval of PADCEV is a significant advance for these patients who previously had limited options after initial therapies failed," said Jonathan E. Rosenberg, MD, medical oncologist and chief of the Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York City.

"The PADCEV clinical trial enrolled a range of patients whose cancer was difficult to treat, including those whose disease had spread to the liver," he said in a statement.

The new approval is based on efficacy and safety data from the EV-201 study, a phase 2 clinical trial involving 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.

The results, first presented at the 2019 American Society of Clinical Oncology annual meeting, indicated an overall response rate (ORR) of 44%, with 12% of patients having a complete response and 32% having a partial response. The median duration of response was 7.6 months.

As reported in June by Medscape Medical News, study investigator Daniel Petrylak, MD, Yale Cancer Center, New Haven, Connecticut, said there is a "high unmet need" among patients with advanced and metastatic urothelial cancer. Despite a flurry of new drug approvals in this setting, with five immune checkpoint inhibitors approved in recent years, the majority of these patients (75%-80%) progress after receiving immunotherapy, said Petrylak.

Data presented at ASCO also indicated that among patients whose cancer had metastasized to the liver, the ORR was 38%; the ORR was 41% in those who had not responded to a checkpoint inhibitor. Median progression-free survival was 5.8 months, and median overall survival was 11.7 months.

Median patient age was 69 years, and 70% were male. Unusually, the primary tumor location was the upper urinary tract in 35% of patients, whereas the tumor was located in the bladder or another location in the remaining 65%.

The most common adverse events of any grade were fatigue (50%), alopecia (49%), decreased appetite (44%), and dyspepsia and peripheral sensory neuropathy (40%). The most common grade 3 or higher events were neutropenia (8%), anemia (7%), fatigue (6%), and maculopapular rash (4%).

The FDA noted that patients treated with enfortumab vedotin may experience hyperglycemia, whether they have diabetes or not, and blood sugar levels should be closely monitored. Patients may also experience eye disorders, including dry eyes and vision changes during treatment. Further, the FDA recommended that healthcare professionals consider prophylactic artificial tears for dry eyes and referral to an ophthalmologist for any new symptoms related to the eye. Patients who experience infusion site extravasation may experience delayed extravasation site reactions with pain, blisters, and peeling of skin.

The FDA advises healthcare professionals to tell patients of reproductive age to use effective contraception during treatment and for a period thereafter. Women who are pregnant or breastfeeding should not take the new drug.

The FDA granted priority review and breakthrough therapy designations for enfortumab vedotin's application. Priority review means that a decision on approval is announced within 6 months; the decision on enfortumab vedotin came through after 3 months.

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