When enfortumab vedotin (now known as Padcev) was initially approved by the FDA in 2019 for use in patients with advanced or metastatic urothelial cancer, it was the first real breakthrough seen in the treatment of bladder cancer in decades. The antibody-drug conjugate works by targeting a protein. Nectin-4, on the surface of cancer cells that helps them stick together and is highly expressed in urothelial cancer cells, as well as other cancers.
Despite its success in the treatment of bladder cancer, with response rates of approximately 40 percent, challenges remain. The drug comes with side effects, including severe skin rash and peripheral neuropathy.
Those side effects are among the factors that motivate the work of Daniel Petrylak, MD, professor of medicine (medical oncology and hematology) and of urology and a pioneer in the research and development of new treatments to fight prostate, bladder, kidney and testicular cancer. His goal is to find ways to make the Padcev treatment easier to tolerate while also increasing its effectiveness for a broader group of patients.
About 90-95% of urothelial cancers are in the bladder. A common symptom is blood in the urine as well as painful or frequent urination, and lower back pain. Urothelial cancers also can develop in the kidney, ureters, or even the urethra.
Dr. Petrylak led several key studies of enfortumab vedotin.
"There was not a lot of enthusiasm at first for the future development of enfortumab vedotin since a lot of research at the time was focused on immunotherapies. However, I had strong confidence in the drug and the positive early responses observed in the Phase I trial. This carried through to Phase II, which led to accelerated approval, and ultimately to Phase III, where it received full approval for clinical use with impressive response rates. Although other agents were being developed, enfortumab vedotin demonstrated the least toxicity," he said.
Hoping to build on this momentum, Dr. Petrylak and others are now looking at new Nectin-4 targeted agents that potentially can reduce toxicity. For example, he is currently the Co-PI on a Phase III international clinical trial looking at bicycle toxin conjugates for the frontline treatment of bladder cancer. This molecule is smaller than antibody-drug conjugates and can potentially penetrate areas that the larger proteins cannot, with more efficacy and less toxicity.
“It is important to acknowledge the side effects that patients are experiencing as they can be very difficult to deal with,” said Dr. Petrylak. “I describe it to my patients that it is like running a race. Skin rash is one of the worst side effects, along with neuropathy, but patients don't want to stop treatment, especially if they're responding. We found that the most crucial thing for progression free survival was maintaining the dose intensity for the first two cycles, after which we can consider dose reduction to lessen the effects.”
The EV-103 trial, which Dr. Petrylak was a co-author on, combined enfortumab vedotin and pembrolizumab (an immunotherapy also known as Keytruda) and showed unprecedented 5-year survival rates for patients.
“We’ve seen remarkable results with this trial, we’re talking doubling survival and overall response rates,” said Dr. Petrylak. “However, the caveat being that 40 percent of patients are alive at five years, so there are patients that are still dying from the disease and there’s still much work to be done.”
Dr. Petrylak is also looking into understanding why some people respond to certain drugs while others don’t. He commented that there are newer agents being looked at that target Nectin-4 in different ways, which is notable because Nectin-4 is more than a bladder specific target; it is also expressed in head and neck cancer, breast cancer, and other tumors as well.
According to Dr. Petrylak, there is a lot in the pipeline to be excited about. He, along with other researchers at Yale, are looking for new targets, new approaches, and are coming at it from all angles. This is particularly important given that Connecticut has the fourth highest incidence rate of bladder cancer in the United States. The lack of screening options and the non-specific nature of symptoms, also often result in cancers being diagnosed at more advanced stages.
"Our momentum is building. Now is not the time to stop. Now is the time to keep pushing and finding newer and better ways to care for patients," Dr. Petrylak said.