A powerful treatment is now an option for many more people with bladder cancer, the fifth most common form of cancer.
The U.S. Food and Drug Administration (FDA) on November 21 approved a combination of two drugs — enfortumab vedotin (Padcev®) and an immunotherapy drug pembrolizumab (Keytruda®), to be given before and after surgery for people with muscle-invasive urothelial carcinoma — a cancer that usually starts in the bladder and can also appear in other parts of the urinary system.
The dramatic results from a phase 3 clinical trial, called KEYNOTE-905, showed the drug combination reduced patients’ risk of death by half, when used before and after surgery to remove the bladder. The patients in the trial had not been treated for muscle-invasive bladder cancer and were either not eligible for or chose not to receive cisplatin-based chemotherapy. (The trial compared the combination therapy plus surgery against surgery alone.)
Although side effects were more common with the combination treatment, the improvement in survival suggested that the benefits outweighed the risks for many patients. The FDA’s new approval significantly increases the number of people with bladder cancer who are eligible for the drug and for intravenous therapy before and after surgery. Enfortumab vedotin had been approved in 2023 for metastatic bladder cancer. Doctors can now use enfortumab vedotin with pembrolizumab for people with earlier-stage disease who cannot receive cisplatin-based chemotherapy, the standard first-line treatment.
“This approval will transform treatment for so many people with bladder cancer,” says Memorial Sloan Kettering Cancer Center (MSK) genitourinary oncologist and bladder cancer specialist Jonathan Rosenberg, MD. “We’ve already seen remarkable results with enfortumab vedotin, and this will help even more patients benefit from it.”
Dr. Rosenberg has led multiple clinical trials testing the drug alone or in combination with others for bladder cancer. Combining enfortumab vedotin with pembrolizumab, an immunotherapy drug called a checkpoint inhibitor, has been especially effective.
Many people with muscle-invasive bladder cancer that has not spread to other parts of the body (stage 2 and stage 3 bladder cancer) undergo bladder-removal surgery (radical cystectomy) as the main treatment. But the cancer returns in about half the patients, requiring further treatment. Many of the patients cannot receive chemotherapy.
The new approval allows doctors to give enfortumab vedotin plus pembrolizumab before and after surgery to reduce the risk of the bladder cancer returning. In some cases, this perioperative treatment will shrink the tumor enough to make surgery possible.
Antibody-Drug Conjugates Deliver a Precise Payload to Cancer Cells
Enfortumab vedotin is a new type of therapy called an antibody-drug conjugate. This type of drug works to treat cancer by combining three parts:
- An antibody that binds to specific proteins or receptors on the surface of the cancer cell.
- A drug, such as chemotherapy, that is toxic to the cancer cell.
- A linker that connects the drug and antibody, keeping the drug bound to the antibody and shielded from the body until it arrives at the cancer cell.
Targeting the Nectin-4 Protein in Bladder Cancer
On a search-and-destroy mission, enfortumab vedotin binds to a protein on cancer cells called nectin-4 and delivers a chemotherapy drug called monomethyl auristatin E. The antibody-drug conjugate selectively delivers monomethyl auristatin E to the cancer cells, killing them while sparing normal body parts from high doses of the drug.
The latest FDA approval marks another major step forward in how antibody-drug conjugates can improve treatment options, even at earlier stages of bladder cancer.
“As an oncologist treating these patients for more than two decades, this feels like a huge sea change in how we treat patients, and hopefully a turning point toward longer survival from this difficult disease,” Dr. Rosenberg says.