Targeting agent enfortumab vedotin a novel treatment for patients with advanced urothelial cancer

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Published: 3 Jun 2019
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Prof Daniel Petrylak - Yale Cancer Center, New Haven, USA

Prof Daniel Petrylak talks to ecancer at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about a study looking at the novel agent enfortumab vedotin targeting Nectin-4 as treatment for patients with advanced urothelial cancer.

He explains that Nectin-4 is a protein that helps cancer cells stick together and it is expressed in 97% urothelial cancers.

Prof Petrylak reports that overall 44% of patients who received the targeting agent responded to treatment and also that a response was seen across the different subgroups.

Watch the press conference here.

Read the news story here.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

There are few available options for the treatment of urothelial cancer once patients have failed primary therapy. The standard approach to treating these patients with metastatic disease includes cisplatinum or carboplatinum, front line chemotherapy followed by checkpoint inhibition therapy. Currently there are five checkpoint inhibitors approved by the FDA in the United States. Unfortunately, only about one in four patients will benefit from receiving a checkpoint inhibitor, thus about three-quarters of patients need other treatment options for their metastatic disease.

In 2013 we started a phase I trial of a drug called enfortumab vedotin in metastatic urothelial cancer. This drug is a smart bomb, it’s a targeted therapy and the target is expressed in approximately 97-100% of bladder cancer specimens. So what the target is is something called Nectin. Nectin is a protein that is an adhesion molecule, it helps cancer cells to stick together. There’s an antibody that targets Nectin and this antibody has been linked to an antitubulin agent called MMAE. This complex is called enfortumab vedotin and this is what we’ve been evaluating.

So in the phase I trial we found that nearly 40% of patients who received enfortumab vedotin responded to the treatment and these are patients who had had checkpoint therapy and prior chemotherapy. Additionally we saw a high response rate, close to 40%, in patients with metastases to the liver. So the EV-201 trial was a study that was designed to evaluate in a larger population of patients, we had 125 patients entered, the enfortumab vedotin drug.

So these are patients, again, who failed either platinum chemotherapy and checkpoint inhibition therapy. Overall we had a 44% response rate that was confirmed on a second measurement. When we look at the different subgroups of patients we see that responses were seen across the board in patients who had prior checkpoint inhibition therapy, patients who had PD-L1 staining or patients from the upper urinary tracts; all these had similar response rates. In fact, those patients who had disease in the liver had a 38% response rate and we had a high complete response rate of 12% and that’s really the highest we’ve seen with any drug.

This was a well-tolerated drug, only 12% of patients discontinued treatment due to adverse events; 6% were due to peripheral neuropathy. These adverse events such as neuropathy, rash and neutropenia are all easily managed and, in fact, with time the neuropathy does resolve and so does the rash.

So we concluded that this is an active drug and based upon the phase I and phase II data we’re filing for accelerated approval with the FDA for enfortumab vedotin. We’re also looking at other ways of administering this drug. There’s a randomised phase III trial comparing enfortumab vedotin to chemotherapy in patients who have received platinum as well as received checkpoint inhibition therapy. There are phase I and phase II trials that are looking at enfortumab vedotin combined with checkpoint inhibition therapy as well as other forms of chemotherapy. So this is a very, very exciting compound, we’re really pleased to see that some of our patients are living for quite some time, in fact from the phase I trial we have two patients who are alive more than three years after they initiated therapy.

We don’t have any viable options for patients who have failed either checkpoint therapy or standard chemotherapy. So my feeling would be that this drug would fit perfectly in those patients and then as we’re beginning to use this drug more I think the drug will be moving up front earlier and particularly in those patients with visceral liver metastases. That’s a group that really does not respond well to standard chemotherapy or immune therapy.