Enfortumab Vedotin & Pembrolizumab Reduce Recurrence Risk in MIBC

For individuals facing muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy, a new combination therapy is offering significant hope. Recent findings demonstrate that treatment with both enfortumab vedotin and pembrolizumab, followed by surgery and then further treatment with the same combination, substantially reduces the risk of recurrence or death compared to surgery alone. This approach has now received FDA approval, marking a notable advancement in the treatment landscape for this aggressive cancer.

Understanding the New Treatment Protocol

The approved regimen involves a neoadjuvant approach – meaning treatment before surgery – with pembrolizumab and enfortumab vedotin-ejfv. Following cystectomy (surgical removal of the bladder) and pelvic lymph node dissection, patients continue with adjuvant treatment, again combining enfortumab vedotin-ejfv with pembrolizumab, before transitioning to pembrolizumab as a single agent. This multi-stage process, evaluated in the KEYNOTE-905/EV-303 clinical trial (NCT03924895), showed statistically significant improvements in both event-free survival (EFS) and overall survival (OS). Details of the trial are available in the New England Journal of Medicine.

Specifically, median event-free survival – the time until the cancer returns or a patient dies – was not yet reached in the pembrolizumab and enfortumab vedotin arm, compared to 15.7 months in the surgery-alone arm. The hazard ratio of 0.40 indicates a nearly 60% reduction in the risk of an event. Similarly, median overall survival was not reached in the treatment arm, while the surgery-alone group had a median OS of 41.7 months, with a hazard ratio of 0.50 suggesting a 50% reduction in the risk of death.

Who Benefits from This Advancement?

This treatment is specifically designed for adults diagnosed with muscle-invasive bladder cancer who are not candidates for, or have declined, cisplatin-based chemotherapy. Cisplatin is a common chemotherapy drug, but it can have significant side effects and isn’t suitable for all patients, particularly those with pre-existing kidney problems or other health concerns. The FDA’s approval notice clarifies this eligibility criterion.

Muscle-invasive bladder cancer is a serious condition where the cancer has grown into the deeper layers of the bladder muscle. It requires aggressive treatment, typically involving surgery to remove the bladder (cystectomy) and often chemotherapy to kill any remaining cancer cells. The challenge lies in identifying the most effective treatment strategies for patients who cannot tolerate or choose not to receive cisplatin.

Delving into the Evidence: Trial Design and Limitations

The KEYNOTE-905/EV-303 trial was an open-label, randomized, multicenter study involving 344 patients. “Open-label” means both the researchers and the patients knew which treatment was being administered. Patients were randomly assigned to either the neoadjuvant pembrolizumab and enfortumab vedotin followed by surgery and adjuvant therapy, or to immediate surgery alone. The primary endpoint was event-free survival, assessed by blinded independent central review – meaning the assessment of outcomes was done by experts who didn’t know which treatment arm a patient was in, reducing potential bias.

It’s key to note the limitations inherent in this type of study. As an open-label trial, there’s a possibility of performance bias – where knowledge of treatment assignment influences patient care or reporting of outcomes. The study population consisted of patients ineligible for or declining cisplatin, meaning the results may not be generalizable to all patients with MIBC. The trial also focused on event-free survival and overall survival, but did not extensively evaluate the impact of the treatment on quality of life.

What Do These Drugs Do? A Closer Look

Pembrolizumab (Keytruda) is an immunotherapy drug. It’s a type of monoclonal antibody that works by blocking the PD-1 protein on immune cells, effectively releasing the brakes on the immune system and allowing it to recognize and attack cancer cells. Enfortumab vedotin-ejfv (Padcev) is an antibody-drug conjugate. This means it combines an antibody that targets a specific protein found on bladder cancer cells with a chemotherapy drug. The antibody delivers the chemotherapy directly to the cancer cells, minimizing damage to healthy tissues. AJMC provides further context on the mechanism of action.

Putting Risk Reduction into Perspective

The reported hazard ratios of 0.40 for event-free survival and 0.50 for overall survival represent substantial reductions in risk. Still, it’s crucial to understand the difference between relative and absolute risk reduction. While a 50% reduction in the risk of death sounds dramatic, the absolute benefit depends on the baseline risk. In the surgery-alone arm, the median overall survival was 41.7 months. The treatment arm has not yet reached median survival, suggesting a potentially significant extension of life, but the exact magnitude of this benefit will require further follow-up.

The Path Forward: Ongoing Research and Surveillance

The FDA approval of this combination therapy is a significant step forward, but the process of refining treatment strategies for MIBC is ongoing. Further research is needed to identify biomarkers that can predict which patients are most likely to benefit from this approach, and to explore potential strategies for overcoming resistance to treatment. Ongoing surveillance of patients treated with this regimen will also be crucial to monitor long-term outcomes and identify any potential late effects.

Clinicians will be integrating this new treatment option into their practice, carefully considering patient eligibility and individual risk factors. Patients diagnosed with MIBC should discuss all available treatment options with their healthcare team to make informed decisions about their care. The National Cancer Institute offers comprehensive information on bladder cancer and its treatment: https://www.cancer.gov/types/bladder.