Advancements in Treating NMIBC: Pembrolizumab FDA-Approved for High Risk Non-Muscle Invasive Bladder Cancer

The United States Food and Drug Administration approved pembrolizumab (Keytruda®) for the treatment of high-risk, nonmuscle invasive bladder cancer (NMIBC) on January 8, 2020. The approval followed results from the Phase II Keynote-057 trial, led by Arjun V. Balar, MD, which found that 40 percent of patients had a complete response (CR). Twenty percent of this subgroup maintained a CR for one year.

“The approval of pembrolizumab in BCG unresponsive HR NMIBC signals the beginning of a new era in the management of localized bladder cancer,” Dr. Balar said. “Patients stand to benefit tremendously with an effective option to treat their disease without necessitating a radical cystectomy and future clinical trials now have a rigorous benchmark against which they will be compared.”
Of the almost 80,000 people who are diagnosed with bladder cancer each year in the United States, it is estimated that 75 percent of cases are NMIBC, a number which makes clear the importance for new therapeutic options like pembrolizumab.

“The approval of pembrolizumab for patients with BCG Unresponsive NMIBC is a win-win situation,” said Ashish Kamat, MD, Ph.D., the Editor of UroToday’s Bladder Cancer Center of Excellence. He added that “it is always beneficial to our patients to have more options, of course.”
In a video for, Dr. Balar noted that the evolution of this trial first began in 2013, when the FDA and the AUA held a workshop for leaders in bladder cancer. “For decades we had been using intravesical BCG, which we know is highly effective. It leads to responses in about 70 to 80 percent of people with carcinoma in situ,” Balar noted. “However, about half of these patients will ultimately either recur or be persistent despite BCG,” he continued. Despite having persistent disease, these patients would often continue to be treated with BCG.

The lack of novel treatments outside of BCG inspired the search for new methods — including the Keynote-057 trial. The trial started in February 2016, with sites accruing high-risk NMIBC patients across the globe. Preliminary results were first presented at ESMO 2018 by Ronald de Wit, MD, Ph.D.

"The FDA approval of Keytruda® for this use is welcome news for patients with bladder cancer. It shows promise for BCG non-responsive patients, giving them another option to having their bladders removed which is a significant quality of life issue,” said Andrea Maddox-Smith, the CEO of the Bladder Cancer Advocacy Network.
In February 2019, Dr. Balar presented the updated results of Keynote-057 at ASCO GU. The study contained two cohorts: Cohort A included patients with CIS with or within papillary disease and cohort B contained patients with papillary disease with no CIS. Every three weeks, patients were given 200 mg of pembrolizumab. They were evaluated with cystoscopy, cytology, and biopsy every 12 weeks for the first two years, and then every 24 weeks for the following two years. The primary endpoints were complete response rates in cohort A, and disease-free survival in cohort B.

The study found that the 3-month complete response rate was 40.2% — with a 3-month complete response rate (CRR) achieved by 41 patients. Of those patients, 58.5% maintained CR at the last follow up. The median CR duration was 12.7 months, according to the presentation at ASCO GU.

After the FDA announced the drug’s approval, Dr. Kamat said that “This approval shows how the FDA has evolved over the years in its understanding of the nuances of NMIBC and post-BCG options. The results of KN057 were the first to be evaluated by a formal ODAC guided by the 2018 FDA guidelines in this disease space, and this process paves the way for future regulatory approvals.”

“This and other recent approvals are good examples of the critical need for continued research to diagnose, treat and monitor bladder cancer,” Andrea Maddox-Smith of BCAN said.

The approval of pembrolizumab also presents the opportunity for further progress. Currently, the Phase III study Keynote-676 is examining BCG with or without pembrolizumab for high-risk NMIBC that is persistent or recurrent following BCG induction — with the hypothesis that the combination will have a superior CRR.

“I'm excited about the prospect of additional immune-based agents to be tested, either alone or in combination with pembrolizumab, which further highlights the impact that immunotherapy has had on this disease across all stages,” Dr. Balar said.
Written by: Gina B. Carithers, Publisher UroToday; and Elise Ryan, Brown University, Providence, Rhode Island