FDA Panel Supports Pembrolizumab for High-Risk NMIBC

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 9 to 4 supporting the approval of a new drug application (NDA) for 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 NDA is based on findings from the phase II KEYNOTE-057 trial (NCT02625961). An FDA analysis of 97 patients from the trial found that pembrolizumab elicited a 41.2% (95% CI, 31.5-51.4) complete response (CR) rate and a median duration of CR of 16.2 months (range, 0.0+ to 26.8+) in this patient population. Nineteen (48%) of the 40 responding patients maintained their response for 1 year or more.

With its affirmative decision, the panel was voting that the response efficacy data compared with the toxicity findings from the KEYNOTE-057 trial demonstrate a favorable risk/benefit profile for pembrolizumab in this setting. The FDA, which is not required to followed the opinion of the ODAC, previously granted a priority review designation to the pembrolizumab NDA with an action date scheduled for January 2020.

“The drug is safe and it does seem to be effective for these patients. I also have a lot of confidence in the physicians counseling these patients to present this as an option, and to present it in the context of what’s known and not known, and for the patients and the doctors to make good decisions about this treatment,” Christian S. Hinrichs, MD, Experimental Transplantation and Immunology Branch, National Cancer Institute, said when explaining his “yes” vote.

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. 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.

Explaining her “no” vote, Andrea B. Apolo, Genitourinary Malignancies Branch, National Cancer Institute, said,“I struggled with this because my patients need better treatments. But I think the data are still early and we need longer follow-up in order to put this into standard treatment options for patients with non-muscle invasive disease."

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.

PEMBROLIZUMAB-P057V01MK3475 Advisory Committee Briefing Document. FDA. https://bit.ly/2r3N3gj. Accessed December 17, 2019.