Immunotherapy Boosts Survival for High-Risk Bladder Cancer Patients

According to the findings of a sizable clinical trial, immunotherapy medication treatment may almost quadruple the amount of time that patients with muscle-invasive, high-risk bladder cancer remain cancer-free after having their bladder surgically removed. The Food and Drug Administration (FDA) has approved pembrolizumab (Keytruda) for the treatment of at least 18 different malignancies. The researchers discovered that this treatment was superior to surveillance after surgery. The National Institutes of Health (NIH) researchers led the study, which was published in the New England Journal of Medicine on September 15, 2024.

“This study shows that pembrolizumab can offer patients another treatment option to help keep their disease from coming back,” said lead investigator Andrea B. Apolo, M.D., of NIH’s National Cancer Institute (NCI) Research”>Center for Cancer Research. “Extending the time that these patients are cancer-free makes a big difference in their quality of life.”

When bladder cancer is diagnosed as muscle-invasive, it indicates that the tumor has spread into and through the layer of muscle tissue that surrounds the bladder. Surgery to remove the bladder entirely is the usual course of treatment for this kind of bladder cancer. Patients are treated with cisplatin-based chemotherapy for a period of time either before surgery, known as neoadjuvant therapy, or after surgery, known as adjuvant therapy, in order to increase the likelihood of a favorable surgical outcome and to eradicate any cancer cells that may have already escaped from the tumor.

Neoadjuvant treatment with cisplatin, however, is often unmanageable or unacceptable for patients with muscle-invasive bladder cancer. Some people are unable to handle adjuvant treatment based on cisplatin. Others have persisting muscle-invasive illness even after receiving neoadjuvant chemotherapy with cisplatin; nonetheless, they are not eligible for adjuvant cisplatin-based chemotherapy treatment. Previously, however, these patient groups were closely watched for indications of relapse.

Rather than waiting for the cancer to return, doctors have started looking at the possibility of prolonging patients’ lives by administering immunotherapy medications following surgery.

After a clinical trial revealed that nivolumab (Opdivo), an immune checkpoint inhibitor that frees T cells to recognize and attack tumors, doubled the median length of time patients remained cancer-free when compared to a placebo, the FDA approved the medication in 2021 as an adjuvant therapy for patients with high-risk, muscle-invasive bladder cancer. The current gold standard of therapy in this context is adjuvant nivolumab.

Researchers looked at whether pembrolizumab, an immune checkpoint inhibitor, might work well as an adjuvant in the present trial. Seventy-two patients who had undergone bladder-removal surgery and had high-risk, muscle-invasive bladder cancer were randomly assigned to either observation for the same duration of time or adjuvant therapy with pembrolizumab every three weeks for a year. In the trial, cisplatin neoadjuvant therapy was completed by about two thirds of the participants.

After a median follow-up of almost four years, patients in the pembrolizumab group remained cancer-free for a median of 29.6 months, compared with 14.2 months for the observation group. The most frequent side effects of pembrolizumab were weariness, itching, diarrhea, and an underactive thyroid. However, the medication was well tolerated.

Immune checkpoint inhibitors, like pembrolizumab, work better against tumors that express a lot of the PD-L1 protein on their surface, or PD-L1-positive tumors, than they do against tumors that do not, or PD-L1 negative tumors, in certain types of cancer. Therefore, Dr. Apolo and her associates evaluated if the impact of pembrolizumab differed according to PD-L1 status.

Pembrolizumab-treated patients among the 404 patients whose tumors tested positive for PD-L1 had a median cancer-free survival of 36.9 months, as opposed to 21 months for the observation group. Pembrolizumab-treated patients among the 298 patients whose tumors were PD-L1-negative had a median cancer-free survival of 17.3 months, as opposed to nine months for the observation group. Given that adjuvant pembrolizumab was beneficial for both groups, the researchers came to the conclusion that patients should not be selected for pembrolizumab treatment based solely on their PD-L1 status.

According to early data on overall survival, at three years, almost 61% of patients in the pembrolizumab group and roughly 62% of patients in the observation group remained alive. It may have distorted the results and complicated the interpretation of the overall survival statistics, the researchers said, because many of the patients in the observation group stopped participating in the study or started using nivolumab after it was approved.

The results of the study are already being expanded upon by research groups investigating adjuvant treatment with different medication combinations that include immune checkpoint inhibitors. Additionally, biomarkers are being tested by researchers to separate out people who may not require adjuvant treatment from those with high-risk, muscle-invasive bladder cancer and determine which patients might benefit most from it.

NCI is the sponsor of the AMBASSADOR trial. Leading and carrying it out is the NCI-funded Alliance for Clinical Trials in Oncology, in which Merck is collaborating with NCI under a Cooperative Research and Development Agreement. Additionally, NCI’s National Clinical Trials Network is involved.

For more information: Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma,

New England Journal of Medicine, doi:10.1056/NEJMoa2401726