New Research Published in New England Journal of Medicine Finds That Adjuvant Pembrolizumab Extends Disease-Free Survival in Muscle-Invasive Urothelial Carcinoma

The AMBASSADOR Phase III clinical trial results, recently published in the New England Journal of Medicine, revealed that adjuvant pembrolizumab (brand name Keytruda), a programmed death 1 (PD1) checkpoint inhibitor immunotherapy, significantly extended disease-free survival in patients with high-risk, muscle-invasive urothelial carcinoma after radical surgery.

Approved by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP), this multi-center trial was conducted by the Alliance for Clinical Trials in Oncology (Alliance) and the National Clinical Trials Network (NCTN). AdventHealth Clinical Research Unit (CRU) Executive Director and Medical Director of Genitourinary Oncology Guru Sonpavde, MD, co-authored the article and served as the lead principal investigator for the Southwest Oncology Group (SWOG), part of the Alliance.

“In our study, the median disease-free survival with pembrolizumab was double that seen with observation, and it also led to an approximately 30% reduction in the risk of the cancer recurring,” shares Dr. Sonpavde. “We continue to make significant advances in immunotherapies that are helping to improve the cure rate for this highly aggressive and difficult to treat cancer.”

The Challenge of Treating Urothelial Cancer

Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. In fact, about 50% of patients with the disease experience recurrence of their cancer after surgery. For many years, the standard of care was radical surgery with neoadjuvant cisplatin-based chemotherapy.

“Neoadjuvant chemotherapy has an overall survival benefit, but many patients are not eligible for this therapy or decline it,” explains Dr. Sonpavde. “Additionally, while we know adjuvant cisplatin-based chemotherapy can lengthen disease-free survival in patients who did not have chemotherapy prior to their surgery, up to one-third of patients are not medically fit to receive chemotherapy post-operatively.”

The Role of Checkpoint Inhibitors

A type of immunotherapy, checkpoint inhibitors have emerged as a new approach to treating cancer. They block specific proteins that prevent the immune system from attacking cancer cells.

In addition to the AMBASSADOR study, several other clinical trials have explored the safety and effectiveness of checkpoint inhibitors in treating patients with urothelial cancer. The CheckMate 274 trial compared adjuvant nivolumab (brand name Opdivo), another PD1 inhibitor immunotherapy, with placebo and demonstrated improvements in disease-free survival, leading to the drug’s approval by the U.S. Food and Drug Administration (FDA) in 2021. More recently, the CheckMate 901 Phase III clinical trial found that combining nivolumab with gemcitabine-cisplatin chemotherapy increased survival rates for patients with unresectable or metastatic urothelial carcinoma.

“Both nivolumab and pembrolizumab are antibodies directed against PD-1, and based on these other studies, we expected to achieve positive results with the AMBASSADOR trial,” says Dr. Sonpavde.

In this latest trial, 702 patients underwent randomization with 354 assigned to receive pembrolizumab and 348 to observation. With a median duration of 44.8 months follow-up, median disease-free survival was 29.6 months with pembrolizumab compared to 14.2 months with observation. The adverse-event profile was consistent with what had previously been reported with no new safety concerns.

“Our findings tell us we’re moving in a good direction, and we’re hopeful that our work will lead to FDA approval of adjuvant pembrolizumab for muscle-invasive urothelial carcinoma within the next 6 months,” reports Dr. Sonpavde.

Additional Research on Treating Urothelial Cancer with Checkpoint Inhibitors

Earlier this year, Dr. Sonpavde and his team at AdventHealth Cancer Institute became one of the first in the world to offer a new, global Phase II clinical trial that is evaluating the efficacy and safety of pembrolizumab plus V940 (mRNA-4157) in patients with high-risk, muscle-invasive urothelial carcinoma of the bladder and upper urinary tract following radical resection. V940 is a novel, customized immunotherapy that consists of mRNA that encodes up to 34 neoantigens (new mutated proteins) found specifically in an individual patient’s tumor. A precision immunotherapy, V940 is designed to activate the immune system to target these neoantigens.

“The V940 trial builds upon what we achieved in the AMBASSADOR trial to see if we can further enhance survival for patients suffering from this aggressive cancer,” comments Dr. Sonpavde. “With this new trial, we’re trying to improve the cure rate for these patients by killing the microscopic cancer cells that remain after surgery."

Dr. Sonpavde believes future research efforts will start to evaluate the use of these new immunotherapies earlier in the disease process. He shared that a study called NIAGARA was recently presented at the European Society of Medical Oncology meeting. It looked at another immunotherapy called durvalumab delivered neoadjuvantly in combination with chemotherapy followed by radical cystectomy and then adjuvant durvalumab in patients with muscle-invasive bladder cancer. The NIAGARA study also demonstrated meaningful improvement in overall survival.

“At AdventHealth, we’re excited about all of these advancements in the quest to cure cancer and remain committed to exploring the potential power of innovative approaches through our research efforts,” states Dr. Sonpavde. “I strongly encourage referral of patients to our many clinical trials, which provide them access to some of the latest treatment options.”