Treatment with the immunotherapy agent pembrolizumab may nearly double the length that patients with high-risk, muscle-invasive urothelial carcinoma are cancer free following surgical removal of the bladder, according to a recent study published by Apolo et al in The New England Journal of Medicine.
Background
A diagnosis of muscle-invasive urothelial carcinoma indicates that the tumor in the bladder has invaded into and through the muscular layer of tissue that encases the bladder. The standard treatment for this type of cancer is surgical removal of the bladder. To improve the chances of successful surgery and of eliminating any cancer cells that may have already escaped from the tumor, patients receive cisplatin-based chemotherapy prior to or following surgery.
However, many patients with muscle-invasive urothelial carcinoma are unable to receive or refuse neoadjuvant chemotherapy with cisplatin, whereas other patients can’t tolerate adjuvant cisplatin-based chemotherapy. Some patients—despite having received neoadjuvant chemotherapy with cisplatin—may have persistent muscle-invasive disease but can’t be treated again with adjuvant cisplatin-based chemotherapy. Historically, these groups of patients were carefully monitored for signs of relapse.
As an alternative to observation, researchers have been investigating the efficacy of adjuvant immunotherapy drugs to determine whether this treatment option can improve cancer-free survival.
In 2021, the U.S. Food and Drug Administration (FDA) approved nivolumab as an adjuvant therapy for patients with high-risk, muscle-invasive urothelial carcinoma after a clinical trial showed that this immune checkpoint inhibitor doubled the median length of time patients remained cancer free compared with placebo. Adjuvant nivolumab is now the standard of care in this setting.
Pembrolizumab has been approved by the FDA for the treatment of at least 18 different cancer types.
Study Methods and Results
In the recent AMBASSADOR study, researchers randomly assigned 702 patients with high-risk, muscle-invasive urothelial carcinoma who had undergone radical surgery to remove the bladder to undergo either adjuvant therapy with pembrolizumab every 3 weeks for 1 year or observation for 1 year. About 67% of the patients involved in the trial had completed neoadjuvant therapy with cisplatin.
After a median follow-up of nearly 4 years, the patients in the pembrolizumab group experienced cancer-free survival for a median of 29.6 months vs 14.2 months among the patients in the observation group. Pembrolizumab was well tolerated, with the most common side effects being fatigue, itching, diarrhea, and an underactive thyroid.
In some cancer types, immune checkpoint inhibitors such as pembrolizumab have proven more effective against tumors that are PD-L1–positive compared with PD-L1–negative tumors. As a result, the researchers assessed whether the effect of pembrolizumab varied by PD-L1 status.
Among the 404 patients with PD-L1–positive tumors, those treated with pembrolizumab experienced cancer-free survival for a median of 36.9 months compared with 21 months among those in the observation group. Among the 298 patients with PD-L1–negative tumors, those treated with pembrolizumab experienced cancer-free survival for a median of 17.3 months compared with 9 months among those in the observation group. The researchers concluded that PD-L1 status should not be used to select patients for treatment with pembrolizumab since both groups benefited from adjuvant pembrolizumab.
After 3 years, the patients who received pembrolizumab experienced overall survival rate of 61% compared with about 62% among the patients who underwent observation. The researchers suggested that many patients in the observation group began taking nivolumab once it was approved or withdrew from the study, which may have skewed the results and made the overall survival data difficult to interpret.
Conclusions
“This study shows that pembrolizumab can offer patients another treatment option to help keep their disease from coming back,” highlighted lead study author Andrea B. Apolo, MD, of the National Cancer Institute’s (NCI) Center for Cancer Research at the National Institutes of Health. “Extending the time that these patients are cancer-free makes a big difference in their quality of life,” she underscored.
The researchers are currently exploring the efficacy of adjuvant treatment using various combination drugs with immune checkpoint inhibitors. They are also testing biomarkers to identify patients with high-risk, muscle-invasive urothelial carcinoma who may benefit most from adjuvant therapy of any kind and spare those who may not need it.
Disclosure: The research in this study was sponsored by the NCI. For full disclosures of the study authors, visit nejm.org.
