Pembrolizumab Plus Enfortumab Vedotin Improves Survival in Bladder Cancer

A novel combination therapy—pembrolizumab plus enfortumab vedotin—is significantly improving survival rates for patients with muscle-invasive bladder cancer, offering a potential shift in treatment paradigms. Data presented at the 2026 ASCO Genitourinary Cancers Symposium demonstrate substantial improvements in both event-free survival and overall survival compared to standard cisplatin-based chemotherapy.

A New Standard of Care?

The KEYNOTE-B15 study, a randomized phase 3 trial, showed that patients receiving neoadjuvant and adjuvant pembrolizumab (Keytruda, Merck) plus enfortumab vedotin-ejfv (Padcev; Astellas Pharma, Pfizer) experienced a 47% improvement in event-free survival (EFS) and a 35% improvement in overall survival (OS) compared to those receiving neoadjuvant cisplatin plus gemcitabine. Pembrolizumab is an immunotherapy drug that helps the body’s immune system attack cancer cells, while enfortumab vedotin is an antibody-drug conjugate that delivers a cytotoxic agent directly to bladder cancer cells.

Currently, neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy (surgical removal of the bladder) is the standard of care for muscle-invasive bladder cancer. Though, approximately half of patients experience metastatic recurrence after surgery, highlighting the need for more effective treatment strategies. This new regimen offers a promising alternative, particularly for patients who may not be eligible for or respond well to cisplatin-based chemotherapy.

Understanding the KEYNOTE-B15 Study

The KEYNOTE-B15 study involved 808 patients with clinically localized muscle-invasive bladder cancer. Patients were randomly assigned to receive either the pembrolizumab plus enfortumab vedotin combination (n=405) or neoadjuvant cisplatin plus gemcitabine (n=403). The treatment regimen involved four cycles of enfortumab vedotin and pembrolizumab before surgery, followed by five cycles of enfortumab vedotin and 13 cycles of pembrolizumab after cystectomy. Event-free survival served as the primary endpoint, with overall survival and pathologic complete response as secondary endpoints.

Notably, the combination therapy also demonstrated a significantly higher pathologic complete response rate—meaning no cancer cells were found in the removed bladder and surrounding tissue—of 55.8% compared to 32.5% in the cisplatin group (P < .0001). This suggests a more effective eradication of the cancer with the new regimen.

Safety Profile and Considerations

While the combination therapy showed promising efficacy, it’s essential to consider the safety profile. The side effects observed were generally manageable and consistent with previous experience with both drugs. Patients receiving enfortumab vedotin plus pembrolizumab experienced higher rates of pruritus (itching), diarrhea, alopecia (hair loss), and rash. However, they had lower rates of anemia, nausea, neutropenia (low white blood cell count), and thrombocytopenia (low platelet count) compared to the cisplatin group.

Matthew D. Galsky, MD, professor of medicine at Mount Sinai, emphasized the significance of these findings, stating, “This represents really the first time since cisplatin-based chemotherapy in the neoadjuvant setting showed improved survival almost 25 years ago that a nonplatinum-based perioperative regimen has surpassed it.”

Expanding Treatment Options: KEYNOTE-905/EV-303

Further bolstering the evidence for this combination therapy, the KEYNOTE-905/EV-303 trial demonstrated improved outcomes with pembrolizumab plus enfortumab vedotin compared to cystectomy alone in patients who were considered ineligible for cisplatin. The FDA approved this regimen in November 2025, expanding treatment options for a broader range of patients. The convergence of these two independent phase 3 studies reinforces the reproducibility and generalizability of the results.

What Does This Mean for Patients?

Muscle-invasive bladder cancer is a challenging disease to treat, and conventional treatments often fall short of preventing recurrence. This new combination therapy offers a potential new standard of care, particularly for patients who may not be suitable candidates for cisplatin-based chemotherapy. The improved event-free survival, overall survival, and pathologic complete response rates suggest a significant benefit for patients receiving this treatment.

However, it’s crucial to remember that this is a complex treatment regimen with potential side effects. Patients should discuss the risks and benefits with their healthcare team to determine if it’s the right option for them. The American Cancer Society provides comprehensive information about bladder cancer treatment options.

Future Directions and Ongoing Research

While the KEYNOTE-B15 study represents a significant advancement in the treatment of muscle-invasive bladder cancer, several questions remain. Researchers are now investigating whether both neoadjuvant and adjuvant therapy are necessary to achieve optimal outcomes. The role of circulating tumor DNA (ctDNA) in predicting treatment response and guiding personalized therapy is also being explored. Research suggests ctDNA may support identify patients who are most likely to benefit from immunotherapy.

As Galsky noted, “We’re in a very different place in this field than we were 5 and 10 years ago…the combination of these drugs and ctDNA, I believe, will usher in the future.” Ongoing clinical trials and research efforts will continue to refine treatment strategies and improve outcomes for patients with muscle-invasive bladder cancer.

William K. Kelly, DO, professor and director of solid tumor oncology at Thomas Jefferson University, echoed this sentiment, stating that the data “provide a compelling rationale” for future studies and represent an “exciting development” in the field.