FDA Approves Pembrolizumab for High-Risk Bladder Cancer

Nick Mulcahy


January 08, 2020

UPDATED with comments January 9, 2020 // The US Food and Drug Administration (FDA) has approved pembrolizumab (Keytruda, Merck) for the treatment of patients with bacillus Calmette-Guérin (BCG)–unresponsive, high-risk, non–muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS).

Specifically, the drug is indicated for patients who are ineligible for or have elected not to undergo the surgical removal of the bladder or cystectomy.

The approval is based on efficacy and safety results from KEYNOTE-057, a multicenter, single-arm trial that enrolled 148 patients with high-risk NMIBC, including 96 who had BCG-unresponsive CIS with or without papillary tumors. Patients received pembrolizumab 200 mg every 3 weeks for up to 24 months without disease progression.

The complete response rate in the 96 relevant patients was 41% (95% confidence interval, 31% to 51%), and the median response duration was 16.2 months, the FDA noted in its announcement. Forty-six percent of responding patients experienced a complete response lasting at least 12 months.

Complete response was defined as having negative results on cystoscopy, urine cytology, and CT urography imaging.

First New Treatment in 20 Years

An estimated 80,000 people develop bladder cancer each year in the United States; a majority of these cases (75%) are NMIBC.

Pembrolizumab is the first new treatment for this type of bladder cancer in 20 years (the previous approval was for valrubicin, in 1998).

"This approval provides a new approach for treating patients with BCG-unresponsive high-risk NMIBC," commented Arjun Balar, MD, associate professor of medicine and director of genitourinary medical oncology at NYU Langone Health's Perlmutter Cancer Center. He was lead investigator of the KEYNOTE-057 study.

"For patients with high-risk NMIBC that has become unresponsive to BCG treatment, the most effective treatment option is a radical cystectomy, which includes removing the entire bladder and a prostatectomy for men or total hysterectomy in women," Balar explained in a Perlmutter release.

"This surgery carries a substantial risk for morbidity and mortality and can negatively impact quality of life," he added. "In fact, many patients are not medically eligible for a radical cystectomy."

Balar noted that the results from KEYNOTE-045 show that 40% of patients had a complete response and that half of those (20%) still had a complete response after 1 year.

"The study demonstrates local activity in the bladder from a systemically administered treatment," Balar noted. "This is promising since systemic immune activation is what ultimately leads to long-term, durable remissions of cancer."

Another expert who was involved in planning the trial, Gary Steinberg, MD, director of Perlmutter Cancer Center’s Urology Bladder Cancer Program, suggested that "the approval of pembrolizumab is paradigm-changing and offers patients a possible therapy to preserve their native bladder function while eliminating their cancer.

"This a breakthrough for some patients and most likely will lead to new combinations of therapy for this aggressive form of localized bladder cancer that will hopefully benefit additional patients," he added.

Steinberg is now heading another study, the KEYNOTE-676 phase 3 study of BCG with or without pembrolizumab for high-risk NMIBC that has persisted or has recurred after BCG induction.

According to the FDA news release, the most common adverse reactions seen with pembrolizumab  were fatigue, diarrhea, rash, pruritis, musculoskeletal pain, hematuria, cough, arthralgia, nausea, constipation, urinary tract infection, peripheral edema, hypothyroidism, and nasopharyngitis.

Pembrolizumab was granted priority review for this indication.

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