What You Need to Know About the FDA's Approval of Keytruda in High-Risk NMBIC


This new option may save patients with high-risk non-muscle invasive bladder cancer from having to undergo a radical cystectomy to treat their disease.

With the Food and Drug Administration (FDA)’s approval of Keytruda (pembrolizumab) for the treatment of patients with a specific subtype of bladder cancer, there may now be hope in sparing those who would otherwise have needed surgery to remove their bladder to treat the disease, according to Dr. Arjun V. Balar.

In particular, the agency recently approved Keytruda for the treatment of patients with Bacillus Calmette-Guerin—unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in-situ with or without papillary tumors who are ineligible for or chose to not undergo cystectomy.

“The hope is that maybe one out of every five patients who otherwise would have had a cystectomy can successfully avoid it, and treat their bladder cancer without this life-altering, potentially very morbid surgery,” Balar said. Balar, who was a lead investigator on the study, and is also an associate professor of medicine and director of genitourinary medical oncology at NYU Langone Health’s Perlmutter Cancer Center, said.

“The research is now expanding such that this is just the beginning of a number of different agents and combinations that will be tested. And ultimately, the goal is that we can limit the number of people who actually need a cystectomy,” he added.

Standard of Care

Carcinoma in situ, which is cancer in the lining of the bladder that has not invaded into the muscle of the organ, is typically managed with Bacillus Calmette-Guérin (BCG) therapy, which is a type of immunotherapy used to treat patients with high-risk non-muscle-invasive bladder cancer after transurethral resection.

“The mechanism, or the way it works, is that you create a liquid with the medicine, and put it inside the bladder. And when it is in the bladder, it actually activates the patient’s immune system, turning on the immune cells — the T cells specifically – and it attacks the abnormal cells in the bladder that are cancerous,” Dr. Matthew Mossanen, from the Division of Urology at Brigham and Women’s Hospital, said in a previous interview with CURE. “In that regard, it is a really clever design because you can put BCG in to the bladder and it activates the immune system, but the bladder itself serves as the perfect barrier to prevent it from getting in to the body.

However, surgery with radical cystectomy (removal of the bladder) is associated with high morbidities and a 5% mortality rate.

“In about 8% of people with carcinoma in situ, (BCG treatment) can lead to a complete response, which means the eradication of the carcinoma site. However, about 50% of those people will still develop recurrence. So, the treatment is not durable,” Balar explained. “So the challenge is what to do with those people who have persistent or recurrent carcinoma in situ within the bladder.”

Because of this patients, can opt for alternative treatment, like intravesical chemotherapy that is administered by installing a bag of chemotherapy, that would typically be administered intravenously, into the bladder. But again, Balar noted, this is rarely a durable treatment option.

KEYNOTE-057 trial

The new drug application for Keytruda in this patient population was based on findings from the phase 2 KEYNOTE-057 trial — designed to evaluate the agent in 96 patients. The primary endpoint was complete response, “which is basically eradication of all carcinoma in situ in the bladder.”

Patients elicited a 41.2% complete response rate and a median duration of complete response of 16.2 months. Nineteen (48%) of the 40 responding patients maintained their response for one year or more. Moreover, Balar said, some of these patients are off of treatment and still experiencing a sustained complete response.

The most common side effects noted in the study were fatigue, diarrhea, rash, pruritis, musculoskeletal pain, hematuria, cough, arthralgia, nausea, constipation, urinary tract infection, peripheral edema, hypothyroidism, and nasopharyngitis.

“The FDA approval is quite meaningful, because at the end of the day, that means that one in five patients may be able to keep their bladder for a long period of time and avoid a cystectomy,” Balar said.

Read CURE’s original coverage of the approval.

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