For patients with locally advanced and metastatic urothelial cancer of the bladder and upper tracts (ureters and renal pelvis), 2024 has been an uncommon and incredibly hopeful year,” says medical oncologist Jean Hoffman-Censits, M.D., co-director of the Upper Tract Urothelial Cancer Multidisciplinary Clinic. “In fact, for the first time ever, the standard of care for this disease has changed!”

Advanced urothelial cancer is the most common form of bladder cancer, and for many years the treatment has been a combination of two drugs: cisplatin and gemcitabine (CG). Now we know that a combination of the anticancer drugs, enfortumab vedotin, plus pembrolizumab (EVP), works much better – thanks to a landmark study, led by Hoffman-Censits and the EV-302 Trial Investigators, published in the New England Journal of Medicine in March 2024.

In this large trial involving nearly 900 patients, scientists from the Greenberg Bladder Cancer Institute, along with colleagues from 185 centers across 25 countries, compared the traditional CG treatment to the EVP combination. “We found that patients treated with EVP lived almost twice as long compared to those treated with CG. The time to cancer progression was significantly longer in the EVP treated group, as well.”

More good news: the investigators found that EVP is “better tolerated by more patients than CG,” says Hoffman-Censits.

The EVP drugs are less toxic because they are highly specific: “Enfortumab vedotin (EV) is in a new class of drug called an antibody-drug conjugate (see below), in which an anticancer drug is attached to a monoclonal antibody that seeks out cancer cells,” Hoffman-Censits explains. “When it finds cancer cells, it binds to a protein on the surface of the cells and directs the cancer-killing drug inside, sparing nearby tissue.” Pembrolizumab is an immunotherapy drug known as a “checkpoint inhibitor.” It unleashes specific immune cells to help the body fight cancer. Based on the study’s strong results, the FDA has approved EVP for the treatment of urothelial cancers.

In related work: Hoffman-Censits and colleagues in Johns Hopkins Rheumatology are learning more about how EV works. “Antibody-drug conjugates are like smart bombs,” she says. A very small payload – traditional cell-killing chemotherapy wrapped in a protective envelope – is attached at the molecular level to an antibody, an immune system weapon with a tiny target: in this case, a molecule called Nectin-4 that sits on the surface of urothelial cancer cells.

Because the target is so individualized, EV delivers the chemotherapy directly to the cancer cell. “This leads to profound cancer shrinkage in many patients, while generally sparing normal tissues,” says Hoffman-Censits.

However, Nectin-4 is also found in the skin. Thus, skin reactions, sometimes severe, are common in nearly half of all patients treated with EV. “EV was FDA-approved (by itself, not in combination with pembrolizumab) for advanced urothelial cancer in 2019, and our team was involved in the early studies leading to this approval. We noted, and were the first to report in the literature, that EV-related skin toxicity seems to correlate with out-comes including response and cancer-related survival.” These results were published in Frontiers in Oncology. “Collection and analysis of these data were possible through efforts of talented postdoctoral fellow Elina Vlachou, M.D., who joins our team from Greece.”