Enfortumab Vedotin Promising Third-Line Option for Metastatic Urothelial Cancer
Chicago, IL—Patients with metastatic urothelial cancer receive first-line treatment with platinum-based chemotherapy and second-line treatment with a checkpoint inhibitor. There is currently no approved third-line therapy for this malignancy. The investigational antibody-drug conjugate enfortumab vedotin may be a good choice for third-line therapy, based on the results of a phase 2 clinical trial presented at ASCO 2019.
In patients with metastatic urothelial cancer whose disease did not respond to treatment with platinum-based chemotherapy and a checkpoint inhibitor, treatment with enfortumab vedotin achieved a response rate of 44%, including 12% complete responses. The median duration of response was 7.6 months.
“The fact that we have a therapy that can help people who don’t benefit from a checkpoint inhibitor is very gratifying,” said lead investigator Daniel P. Petrylak, MD, Disease Aligned Research Team Leader, Prostate and Urologic Cancers Program, Yale Cancer Center, Yale School of Medicine, New Haven, CT.
“This study addresses a high unmet need. Enfortumab is the first novel therapy to demonstrate substantial clinical activity in patients who progressed after platinum-based chemotherapy and PD-1 or PD-L1 inhibitor. Enfortumab may have the potential to become a new standard of care for patients who progress on platinum and checkpoint inhibitor,” Dr Petrylak added.
Dr Petrylak noted that this new antibody-drug conjugate is undergoing further evaluation. Ongoing phase 3 clinical trials are comparing enfortumab vedotin versus investigator’s choice of chemotherapy, and phase 1 clinical trials are beginning to explore its use in combination with other agents.
Enfortumab Mechanism of Action
Enfortumab vedotin targets nectin-4, a cellular adhesion molecule with low expression in normal cells but with upregulation in urothelial cancer cells and other solid tumors. Enfortumab vedotin binds to nectin-4, and delivers chemotherapy, leading to apoptosis of cancer cells. In 2018, the FDA granted enfortumab vedotin breakthrough therapy designation for locally advanced or metastatic urothelial cancer.
The phase 2 EV-201 clinical trial is being conducted at 51 international sites. At ASCO, Dr Petrylak presented results of Cohort 1, which included 128 platinum-eligible patients (median age, 69 years; 70% male) with locally advanced or metastatic urothelial cancer, who had previously received platinum-based therapy and a checkpoint inhibitor.
A total of 90% of patients had visceral metastases, including 40% liver metastases. All patients had disease associated with nectin-4, and 35% of patients had PD-L1 expression.
The intent-to-treat analysis included data for 125 patients. The objective response rate was 44%, including 12% complete responses and 32% partial responses. On a waterfall plot, 84% of the patients had some form of tumor shrinkage, as measured by computed tomography scans. All prespecified subgroups responded to treatment with enfortumab vedotin, including 38% of the patients with liver metastases.
The responses occurred quickly. The median time to response was 1.8 months, and the median duration of response was 7.6 months. The median progression-free survival was 5.8 months, and the median overall survival was 11.7 months.
Enfortumab vedotin was generally well-tolerated, with mainly grades 1 and 2 adverse events. The most common events of any grade were fatigue (50%), alopecia (49%), decreased appetite (44%), dysgeusia (40%), and peripheral sensory neuropathy (40%). The most common grade 3 or 4 adverse events were neutropenia (8%), anemia (7%), and fatigue (6%). A total of 12% of the patients discontinued treatment because of adverse events.
“Metastatic urothelial cancer is common, yet we have limited therapeutic options. For decades, all we had was chemotherapy. Now we have second-line checkpoint inhibitor therapy, but basically 1 in 4 patients respond,” said ASCO expert Robert Dreicer, MD, MS, MACP, FASCO, Deputy Director, University of Virginia Cancer Center, Charlottesville, who commented on the study.
“New therapies are badly needed, and I find these data on enfortumab compelling. The drug has activity in patients treated with prior chemotherapy and immunotherapy, as well as activity in disease sites considered hard to treat like the liver. Survival approaches 1 year,” Dr Dreicer said.
He added, “We are seeing durable responses in heavily treated patients. The response rate in patients with liver metastases is the ultimate test that this agent has good activity. These patients represent an unmet need, and there is no question that this drug will benefit patients. I am hopeful that the phase 3 studies will pan out.”