FDA Approves Pembrolizumab for BCG-Unresponsive NMIBC

Oncology, ONCOLOGY Vol 34 Issue 2, Volume 34, Issue 2

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

The FDA  approved pembrolizumab (Keytruda) for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or chose to not undergo cystectomy.1 “This is a major advance,” lead study investigator Arjun V. Balar, MD, associate professor of medicine and director of the genitourinary medical oncology program at NYU Langone Health’s Perlmutter Cancer Center told ONCOLOGY. “While cystectomy is highly curative, there is a substantial impact on short and long-term quality of life with the surgery and high rates of complications as well, including an approximately 5% rate of mortality.”

The approval, which was based on findings from the phase II KEYNOTE-057 trial (NCT02625961), follows the 9-4 favorable vote in December 2019 from the FDA’s Oncologic Drugs Advisory Committee that supporting the approval of the new drug application for pembrolizumab.2 The FDA recommended a dose of 200 mg every 3 weeks. “This approval proves that systemic immunotherapy is active in a “localized” cancer process and has ushered the development of new treatments that could be combined with immunotherapy for the further benefit of patients with this disease,” said Balar.

Pembrolizumab is the first new drug approved for BCG-unresponsive high-risk NMIBC since 1998. Prior to this approval, cystectomy was usually recommended to patients. “A substantial proportion would outright refuse the surgery, and opt for other less effective treatments, which would then compromise their care,” acknowledged Balar. “With the approval of pembrolizumab, we have an effective option after BCG which will enable more patients to safely avoid a cystectomy.”

KEYNOTE-057 Trial

The multicenter, open-label, single-arm, multicohort phase II KEYNOTE-057 trial enrolled 102 patients with BCG-unresponsive, high-risk, NMIBC with CIS with or without papillary tumors who were ineligible for or did not undergo cystectomy. “The primary efficacy outcome measure was the proportion of patients achieving a complete response (complete eradication),” Balar said.

Key secondary endpoints were duration of response and safety.

In cohort A, 96 patients were administered pembrolizumab 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or disease progression. Disease was assessed every 12 weeks, and those who did not have disease progression could receive treatment for up to 2 years. Pembrolizumab elicited a CR rate of 41.2% (95% CI, 31.5-51.4), with a median duration of CR of 16.2 months (range, 0.0 to 26.8). Nineteen (48%) of the 40 responding patients maintained their response for 1 year or more.

At an updated median follow-up of 21.1 months (range, 4.6-33.4), treatment was ongoing in 11 patients. Eighty-eight patients discontinued pembrolizumab due to persistent disease (n = 40), recurrent disease (n = 33), adverse events (AEs; n = 10), achieved CR (n = 2), physician decision (n = 1), protocol violation (n = 1), and patient withdrawal (n = 1). The most common AEs (incidence ≥10%) were fatigue, diarrhea, rash, pruritis, musculoskeletal pain, hematuria, cough, arthralgia, nausea, constipation, urinary tract infection, peripheral edema, hypothyroidism, and nasopharyngitis.

“Treatment with pembrolizumab is generally very well tolerated, with up to [one-]third of patients reporting no side effects,” according to Balar. “However, clinicians should be aware that immunotherapy treatment can lead to immune-related side effects. Severe side effects from the immune system are rare, but important to recognize quickly. [Because] any organ system can be affected by the immune system, a clinician must be aware that any symptom that is new while on treatment with immunotherapy could be an immune-related side effect.”

Pembrolizumab is currently being tested in a similar population of patients in the ongoing phase III KEYNOTE-676 trial. “Specifically, [this trial] is evaluating BCG with or without pembrolizumab in patients who have persistent [high-risk] NMIBC after 1 course of induction BCG,” said Balar. “The goal is to evaluate if its use in combination with BCG further improves outcomes.”







1. FDA website. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer. Published January 8, 2020. Accessed February 3, 2020.

2. FDA website. PEMBROLIZUMAB-P057V01MK3475 Advisory Committee Briefing Document. https://www.fda.gov/media/133542/download. Published December 17, 2019. Accessed February 3, 2020.