A new combination therapy is showing significant promise in the fight against muscle-invasive bladder cancer, a disease that affects thousands each year. Results from a major clinical trial demonstrate that using the drugs enfortumab vedotin and pembrolizumab both before and after surgery dramatically improves survival rates and the likelihood of complete cancer removal compared to standard chemotherapy. This represents a potential shift in how doctors approach this aggressive cancer, offering new hope for patients facing a difficult diagnosis.
The findings, presented at the 2026 ASCO Genitourinary Cancers Symposium in San Francisco, California, on February 27, 2026, come from the phase III KEYNOTE-B15/EV-304 study. Researchers followed 808 patients with muscle-invasive bladder cancer who were eligible for cisplatin-based chemotherapy and subsequent radical cystectomy – surgical removal of the bladder – plus pelvic lymph node dissection. The study focused on patients whose cancer had not yet spread to distant parts of the body, but had grown into the muscle layer of the bladder wall.
A New Approach to Bladder Cancer Treatment
Traditionally, patients with muscle-invasive bladder cancer have received neoadjuvant chemotherapy – treatment given before surgery – consisting of cisplatin and gemcitabine. However, the KEYNOTE-B15/EV-304 trial tested a different approach: neoadjuvant enfortumab vedotin plus pembrolizumab, followed by surgery, and then continued treatment with the same combination afterward. Enfortumab vedotin is a targeted drug that delivers a chemotherapy agent directly to cancer cells expressing the NECTIN4 protein, while pembrolizumab is an immunotherapy drug that helps the body’s own immune system recognize and attack cancer cells. Immunotherapy has turn into increasingly key in cancer treatment over the past decade.
The results were compelling. The median time from randomization to the data cutoff of October 27, 2025, was 33.6 months. Patients receiving enfortumab vedotin plus pembrolizumab experienced a significant improvement in event-free survival – meaning they lived longer without the cancer returning or progressing. Median event-free survival was not yet reached in the enfortumab vedotin plus pembrolizumab group, compared to 48.5 months in the cisplatin plus gemcitabine group. At 24 months, 79.4% of patients on the new combination were still event-free, compared to 66.2% in the standard chemotherapy group (HR = 0.53, 95% confidence interval [CI] = 0.41–0.70; 1-sided P < .0001).
Improved Survival and Pathologic Response
Beyond event-free survival, the study also showed improvements in overall survival. Estimated 24-month survival rates were 86.9% with enfortumab vedotin plus pembrolizumab versus 81.3% with cisplatin plus gemcitabine (HR = 0.65, 95% CI = 0.48–0.89; 1-sided P = .0029). While median overall survival hasn’t been reached in either group yet, the trend strongly favors the new combination. Perhaps most strikingly, the rate of pathologic complete response – meaning no cancer cells were found in the bladder or lymph nodes after surgery – was significantly higher in the enfortumab vedotin plus pembrolizumab group (55.8% vs 32.5%; estimated difference = 23.4%, 95% CI = 16.7%–29.8%; 1-sided P < .0001).
“These results are really exciting since they show a substantial benefit in terms of both preventing the cancer from coming back and improving overall survival,” explained Dr. Matthew D. Galsky, of Mount Sinai Tisch Cancer Center, who presented the study findings.
Matthew D. Galsky, MD, FASCO
Balancing Benefits and Side Effects
As with any cancer treatment, Notice side effects to consider. Grade 3 or higher treatment-emergent adverse events occurred in 75.7% of patients receiving enfortumab vedotin plus pembrolizumab, compared to 67.2% of those receiving cisplatin plus gemcitabine. The most common severe side effects associated with enfortumab vedotin were skin reactions (14.1%), while severe skin reactions were the most common with pembrolizumab (13.9%). These side effects, while manageable, require careful monitoring and supportive care.
Wm. Kevin Kelly, DO, FASCO, an ASCO Expert in genitourinary oncology and Professor of Medical Oncology at Thomas Jefferson University, emphasized the significance of the study. 
Wm. Kevin Kelly, DO, FASCO
