FDA Grants Pembrolizumab Priority Review for High-Risk NMIBC

The FDA has granted a priority review designation to pembrolizumab for the treatment of patients with Bacillus Calmette-Guerin–unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in-situ with or without papillary tumors who are ineligible for or chose to not undergo cystectomy.

Roy Baynes, MD, PhD

The FDA has granted a priority review designation to 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

The decision is based on findings from the phase II KEYNOTE-057 trial (NCT02625961), which were initially presented at the 2019 ESMO Congress. Updated results, which were presented at the 2019 ASCO Annual Meeting, demonstrated that pembrolizumab elicited a 41.2% complete response (CR) rate and a median duration of CR of 13.5 months (range, 0.0+ to 26.8+) in this patient population.2

The data will be discussed during a meeting of the FDA’s Oncologic Drugs Advisory Committee that will take place on December 17, 2019. Merck, the developer of the PD-1 inhibitor, stated in a press release that it anticipates the agency to decide on the approval in January 2020.

“Merck is steadfast in its commitment to patients with bladder cancer, including advancing research to meet unmet medical needs. Patients with high-risk, non-muscle invasive bladder cancer sometimes make an informed decision to decline, or are medically ineligible for radical cystectomy, and there are currently limited nonsurgical treatment options approved by the FDA for these patients who are BCG-unresponsive,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, stated in the press release. “We look forward to participating in the advisory committee meeting and to continuing to work with the FDA as they review this supplemental application for Keytruda.”

In the multicenter, open-label, single-arm, multicohort, phase II KEYNOTE-057 trial, investigators 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 (cohort A). Cohort B consists of 130 patients with papillary disease without CIS.

Pembrolizumab was administered at 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.

The median age was 73 years (range, 44-92), with most patients (70.6%) ≥65 years. Most patients (83.3%) were male, 67.6% were white, and 73.5% had an ECOG performance status of 0. The median number of prior BCG instillations was 12 (range, 6-45). Patients had CIS with T1 (11.8%), CIS with high-grade Ta (24.5%), or CIS alone (63.7%). More than half of patients (56.9%) had a PD-L1 combined positive score <10, and the reason most patients did not have prior cystectomy was because they refused (95.1%). The baseline high-risk NMIBC disease status was recurrent in 69.6% of patients.

The primary outcome measures were CR, urine cytology, and computed tomography urography imaging, and duration of response. The enrollment cutoff date was April 1, 2018.

Interim data demonstrated a 3-month CR rate of 38.8% in this patient population.3 Among the 40 patients who achieved a CR at 3 months, 72.5% maintained a CR at a median follow-up of 14 months; the median CR duration had not been reached. A total 80.2% of patients had a CR lasting ≥6 months.

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).

Twenty-two of the 42 patients who achieved CR had an ongoing response at the time of data cutoff, and 20 of these patients subsequently experienced recurrent disease. One patient experienced recurrent disease immediately after ≥2 nonevaluable assessments; they discontinued after 12 weeks due to ongoing AEs. Additionally, 1 patient with a locally assessed CR underwent cystectomy, and another was nonevaluable at week 12 but then had a confirmed CR at the start of week 24 with >12 months of durability. No patients developed muscle-invasive or metastatic disease.

Higher CRs were observed in patients who were not white (55.6%) and an ECOG performance status of 1 (51.9%); they were lowest in those who had CIS with high-grade Ta (28.0%).

The safety profile was found to be consistent with AEs that were reported in prior studies of the PD-1 inhibitor. Ninety-nine patients experienced ≥1 AE, and treatment-related AEs (TRAEs) were reported in 65.7% of patients. Grade 3 to 5 AEs, grade 3/4 TRAEs, serious AEs, and serious TRAEs were reported in 29.4%, 12.7%, 24.5%, and 7.8% of patients, respectively. Two patients died.

Grade 3/4 cases of hyponatremia and arthralgia was observed in 3 and 2 patients, respectively. There was 1 case each of grade 3/4 adrenal insufficiency, severe skin reaction, and type 1 diabetes mellitus.

The ongoing KEYNOTE-676 trial (NCT03711032) is evaluating pembrolizumab plus BCG in patients with high-risk NMIBC that is persistent or recurrent after BCG induction therapy.

Pembrolizumab is currently approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are ineligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) ≥10], or in patients who are ineligible for any platinum-containing chemotherapy regardless of PD-L1 status. The PD-1 inhibitor is also approved for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.


  1. FDA Grants Priority Review to Merck’s Supplemental Biologics License Application (sBLA) for KEYTRUDA® (pembrolizumab) in Certain Patients with High-Risk, Non-Muscle Invasive Bladder Cancer (NMIBC). Merck. Published December 2, 2019. https://bit.ly/2Y6WNm1. Accessed December 2, 2019.
  2. De Wit R, Kulkarni GS, Uchio EM, et al. Pembrolizumab (pembro) for patients (pts) with high-risk (HR) non—muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG): Updated follow-up from KEYNOTE-057. J Clin Oncol. 2019;37(suppl; abstr 4530). doi: 10.1200/JCO.2019.37.15_suppl.4530.
  3. Balar AV, Kulkarni GS, Uchio EM, et al. KEYNOTE 057: phase II trial of pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guérin (BCG). J Clin Oncol. 2019;37(suppl 7, abstr 350). doi: 10.1200/JCO.2019.37.7_suppl.350.