Overview of Enfortumab Vedotin in Urothelial Carcinoma

Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology at Queen Mary University of London; director, Barts Cancer Center, discusses the mechanism of action of enfortumab vedotin-ejfv (Padcev) and its use in treating locally advanced or metastatic urothelial carcinoma (mUC).

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0:09 | Enfortumab vedotin is an antibody-drug conjugate. It is an exciting drug in urothelial cancer. Antibody-drug conjugates essentially have 3 components. They have the targeted antibody, they have a linker molecule, and a payload attached to that. The antibody acts as a homing device to attach, essentially, to the cancer. In the case of enfortumab vedotin, that antibody is Nectin-4. It binds to Nectin-4, and about 98% of urothelial cancers overexpress Nectin-4. It's also important to recognize that other organs overexpress Nectin-4, like the skin, and that is why there's some skin toxicity with the drug.

0:55 | The linker molecule attaches the payload, and MMAE is the payload. That is essentially a microtubule disrupting agent, which is a type of chemotherapy. The drug therefore is an antibody-drug conjugate; it was tested in phase 1, phase 2, and phase 3 as a monotherapy. The key to that data is that it was tolerable as a monotherapy and associated with a 30% reduction in the risk of death in patients with heavily-treated urothelial cancer in a randomized phase 3 trial vs chemotherapy. It became the standard-of-care in patients whose cancers have progressed after chemotherapy and immunotherapy.

1:45 | The drug as a single agent is associated with adverse event profiles. The adverse events of special interest are the skin toxicity, peripheral neuropathy, and hyperglycemia. There are other components, some nausea and fatigue, and there's not really too much interstitial pneumonitis like what people talk about with antibody-drug conjugates. It is actually not that common with enfortumab vedotin. The toxicity is manageable, and the drug as a monotherapy was given on day 1, day 8, and day 15 in a 4-week cycle. The drug is associated with a 40% response rate, which is much higher than other agents that we've seen in this disease. Normally, immunotherapy is about 20%, chemotherapy about 10%-15%. We knew it was a great drug, and we feel as a monotherapy, in my opinion, it is probably the best drug that we have.