A groundbreaking clinical trial has shown that treatment with the immunotherapy drug pembrolizumab (Keytruda) nearly doubles the time patients with high-risk muscle-invasive bladder cancer remain cancer-free after bladder removal surgery. The study, led by researchers from the National Institutes of Health (NIH), found that the drug outperformed standard observation, offering new hope for patients who cannot tolerate traditional chemotherapy. The trial results were published on September 15, 2024, in the New England Journal of Medicine.

Pembrolizumab, already approved by the U.S. Food and Drug Administration (FDA) for treating at least 18 different cancers, was shown to extend the cancer-free period in patients who had undergone surgery for bladder cancer. Dr. Andrea B. Apolo, the lead investigator and a researcher at the National Cancer Institute (NCI), explained that the results provide a promising treatment option for bladder cancer patients.

Muscle-invasive bladder cancer is a severe form of the disease in which the tumor penetrates through the muscle layer surrounding the bladder. Standard treatment involves the surgical removal of the bladder. To improve outcomes, many patients receive cisplatin-based chemotherapy either before surgery (neoadjuvant therapy) or after (adjuvant therapy). However, a significant number of patients are either ineligible for cisplatin or cannot tolerate it, leaving observation as the only option. This group has long needed alternative treatments to reduce the risk of cancer recurrence.

Researchers have been exploring the use of immunotherapy as an adjuvant treatment for muscle-invasive bladder cancer, hoping it can extend patients’ cancer-free periods. In 2021, the FDA approved the immune checkpoint inhibitor nivolumab (Opdivo) for this purpose after it was shown to double the median cancer-free time in patients when compared with a placebo. Adjuvant nivolumab became the new standard of care.

The current trial, known as the AMBASSADOR study, examined whether pembrolizumab could also serve as an effective adjuvant treatment. A total of 702 patients with high-risk muscle-invasive bladder cancer who had undergone bladder-removal surgery were randomly assigned to receive either pembrolizumab every three weeks for one year or observation over the same period. Two-thirds of the participants had already completed neoadjuvant cisplatin-based chemotherapy before surgery.

After a median follow-up period of nearly four years, the study found that patients treated with pembrolizumab remained cancer-free for a median of 29.6 months, compared to just 14.2 months for those under observation. Pembrolizumab was generally well tolerated, with common side effects including fatigue, itching, diarrhea, and hypothyroidism.

The study also investigated whether the effectiveness of pembrolizumab varied based on the presence of PD-L1 protein, which is known to influence the response to immune checkpoint inhibitors. Among the 404 patients whose tumors were PD-L1-positive, those treated with pembrolizumab remained cancer-free for a median of 36.9 months, compared to 21 months for the observation group. For the 298 patients whose tumors were PD-L1-negative, the median cancer-free time was 17.3 months for the pembrolizumab group, compared to nine months for those under observation.

Based on these findings, the researchers concluded that PD-L1 status should not be used as a determining factor for pembrolizumab treatment, as both groups saw significant benefits.

Although preliminary data on overall survival showed similar rates between the pembrolizumab and observation groups, researchers noted that many patients in the observation group had started receiving nivolumab after its approval, which may have impacted the results.

The study’s findings are already influencing further research, with teams exploring combinations of immune checkpoint inhibitors and other drugs to enhance treatment effectiveness. Additionally, efforts are underway to identify biomarkers that can help determine which patients are most likely to benefit from adjuvant therapies like pembrolizumab, potentially sparing others from unnecessary treatment.

The AMBASSADOR study was sponsored by NCI and conducted by the Alliance for Clinical Trials in Oncology. It was part of a collaboration between Merck, the manufacturer of pembrolizumab, and NCI under a Cooperative Research and Development Agreement.

References:

1. Powles, Thomas, James W.F. Catto, Matthew D. Galsky, Hikmat Al-Ahmadie, Joshua J. Meeks, Hiroyuki Nishiyama, Toan Quang Vu, et al. 2024. “Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer.” New England Journal of Medicine, September. https://doi.org/10.1056/nejmoa2408154.

“Pembrolizumab improves outcomes in high-risk bladder cancer.” 2024. Cancer.Gov. September 16, 2024. https://www.cancer.gov/news-events/press-releases/2024/high-risk-bladder-cancer-pembrolizumab.

(Rehash/Ankur Deka/MSM)