A novel combination therapy with first-in-human roots at the University of Colorado Anschutz delivered effective and durable responses in patients with advanced, muscle-invasive bladder cancer (MIBC), according to a new study in the New England Journal of Medicine. The statistically significant results of the multi-site, phase-3 clinical trial signal a potential new standard of care for this dangerous stage of bladder cancer.
The study involved over 800 patients, lasted nearly three years and spanned clinical sites in the United States, Europe, Asia and Australia. It culminates a CU Anschutz-involved effort in the establishment of this groundbreaking regimen as a first-line treatment for metastatic bladder cancer – and now potentially for muscle-invasive bladder cancer as well.
A few years ago, the same combination – an antibody conjugate with an immunotherapy drug – resulted in 65% to 70% positive responses for patients, across various clinical trials, with advanced or metastatic urothelial cancer. The phase-1, first-in-human study, published in 2023 in the Journal of Clinical Oncology, showed that most patients experienced tumor shrinkage and median overall survival beyond two years.
“This study takes this combination, which has been the preferred regimen for metastatic disease, and investigates its role in muscle-invasive bladder cancer, which is where the disease becomes a lethal threat,” said Thomas Flaig, MD, CU Anschutz vice chancellor for research, who is a co-author on the new study and a principal investigator on the 2023 study.
The new study compared the effectiveness of the standard treatment, cisplatin-gemcitabine chemotherapy, with the combination of enfortumab vedotin (an antibody drug conjugate) and pembrolizumab (an immune checkpoint inhibitor). At two years, an estimated 79.4% of the 405 participants in the enfortumab vedotin-pembrolizumab (EVP) group were alive and showed no recurring cancer, compared to 66.2% of the 403 participants in the cisplatin-gemcitabine group.
There was no sign of tumor in 55.8% of participants in the EVP group compared to 32.5% in the cisplatin group at the time of surgery.
EVP’s overall positive patient results in previous studies of later-stage disease established it as “the sole preferred candidate” for treatment of advanced bladder cancer, Flaig said.
Bladder cancer in the U.S.
In the United States, there were about 84,870 new cases of bladder cancer and 17,420 deaths from the disease in 2025, according to the American Cancer Society. Metastatic bladder cancer has a five-year survival rate of about 10%.
Flaig is chair of the National Comprehensive Cancer Network Guidelines Panel for Bladder Cancer and member of the CU Anschutz Cancer Center. He said systemic therapies for bladder cancer leaped forward in 2017, starting with the development of immune checkpoint inhibitors and then antibody drug conjugates.
“It’s a much more hopeful time for bladder cancer patients,” he said. “If you look back to a decade ago, we couldn’t complete trials, and we weren’t approving new drugs. Fast-forward to today, we’ve got many new approved drugs, including this very important combination. We’ve got improved outcomes for patients, and a lot of activity and interest in developing new drugs. Although we’ve got a long way to go, it’s certainly a more optimistic time in the sense that we can identify issues and improve them in bladder cancer.”
Definitions:
- Muscle-invasive bladder cancer: A type of bladder cancer that has grown into the muscle layer of the bladder wall and is more aggressive than early-stage disease.
- Combination therapy: A treatment approach that uses two or more therapies together to improve effectiveness.
- First-in-human trial: The first stage of clinical research where a new treatment is tested in people after preclinical studies.
The road to this EVP combination therapy, which has now gained steam for muscle-invasive disease (roughly 25% of all bladder cancers) as well as metastatic bladder cancer, began at CU Anschutz. “We were one of the sites in the 2023 study, called EV103, that first looked at that combination together,” Flaig said. “In fact, we treated one of the very first patients in the world with this combination.”
The combination therapy works by delivering a dual attack on bladder cancer cells.
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The antibody drug conjugate uses an antibody to guide it to a target marker on the cancer cell – a protein called nectin-4. Once attached to the protein, the antibody drug conjugate delivers chemotherapy to kill the cancer cell. The pembrolizumab, meanwhile, counteracts the cancer cells’ ability to express a protein that turns off the immune system. Flaig said the drug is able to “disable the parking brake, so this car – the immune system – can start rolling again” and attack the cancer cells.
Because the drug is releasing the immune system, a potential downside of EVP treatment is autoimmune disease – or the body essentially attacking itself. Enfortumab vedotin, the antibody drug conjugate, can also cause neuropathy and numbness in the extremities.
Despite the potential side effects, EVP ushers in a new era of improved outcomes for patients with advanced-stage bladder cancer.
“For me, the cool part is that we’ve gone from phase 1 to a positive phase 3 study, and we have been able to be involved throughout this development,” Flaig said.
Key points:
- In the United States, there were about 84,870 new cases of bladder cancer and 17,420 deaths from the disease in 2025.
- Research began with first-in-human trials at CU Anschutz.
- Systemic therapies for advanced bladder cancer leaped forward in 2017, starting with the integration of immune checkpoint inhibitors and then antibody drug conjugates.
- In a recent multi-site, multi-year clinical trial, a combination therapy of an antibody drug conjugate (enfortumab vedotin) and an immune checkpoint inhibitor (pembrolizumab) delivered significantly improved outcomes for patients with muscle-invasive bladder cancer.
- This combination therapy ushers in a new era of care for patients with advanced-stage bladder cancer.