Pembrolizumab Active in BCG-Unresponsive NMIBC

Ronald de Wit, MD, PhD

An interim analysis of an ongoing single-arm open-label phase II study showed encouraging antitumor activity with pembrolizumab (Keytruda) in patients with high-risk nonmuscle invasive bladder cancer (NMIBC) that is unresponsive to Bacillus Calmette-Guérin (BCG) who refused or were ineligible for cystectomy.

The rate of complete response (CR) in the first 103 patients enrolled with carcinoma in situ (CIS), with or without papillary disease, was 38.8% at 3 months, with 80% of patients having a duration of CR ≥6 months,1 said Ronald de Wit, MD, PhD, at the 2018 ESMO Congress.

Of the patients with recurrence of high-risk NMIBC, none progressed to muscle invasive or metastatic bladder cancer, said de Wit, group leader of the Experimental Systematic Therapy of Urogenital Cancers program at Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

High-risk NMIBC is defined as carcinoma in situ, T1 tumor, and grade Ta tumor. The CR rate to standard of care transurethral resection of bladder tumor and intravesical BCG therapy in patients with high-risk NMIBC is approximately 70%, but most patients with high-risk disease experience recurrence, and 30% will have recurrence within 1 year.

The need for novel therapies to reduce the risk of recurrence and preserve the bladder is urgent. “If not properly managed, 40% of patients at high risk progress to muscle invasive disease, and eventually 20% to 30% progress to metastatic disease,” said de Wit. “So this is not a benign disease. NMIBC is a potentially life-threatening disease.”

Radical cystectomy is recommended for BCG-unresponsive high-risk NMIBC because of the risk for disease progression. “However, it is associated with significant morbidity and mortality and a negative impact on quality of life, and many patients actually refuse or are ineligible for cystectomy,” he said.

BCG-refractory disease is defined as stage progression at 3 months after adequate BCG induction after initial CIS or high-grade Ta or persistent high risk NMIBC at 6 months despite adequate BCG. (Adequate BCG therapy is defined as at least 5 of 6 instillations of induction BCG plus at least 2 of 3 doses of maintenance therapy or 2 of 6 doses of a second induction course.) BCG-relapsing disease is defined as recurrence of high-risk NMIBC after the patient achieves a disease-free status 12 months after adequate BCG therapy.

Activation of the PD-1 pathway has been implicated in resistance to BCG therapy. The PD-1 inhibitor pembrolizumab has demonstrated significant antitumor activity in patients with metastatic urothelial carcinoma, but little was known about anti—PD-1 monotherapy for NMIBC.

KEYNOTE-057 is a single-arm open-label phase II study enrolling patients with high-risk NMIBC unresponsive to BCG who refuse or are ineligible for cystectomy. “With the lack of a suitable comparator, single-arm designs have been found suitable in the BCG-unresponsive population,” said De Wit.

Patients with papillary disease must have had fully resected disease at study entry. The study comprised 2 cohorts. de Wit presented data from cohort A, which comprised 130 patients with CIS with or without papillary disease (high-grade Ta or T1). Cohort B consisted of 130 patients with papillary disease without CIS.

Patients received pembrolizumab at 200 mg every 3 weeks. They were evaluated by cystoscopy and cytology with or without biopsy every 12 weeks for 2 years plus a computed tomography urogram every 24 weeks for 2 years.

Assessments and pembrolizumab treatment continued until recurrence of high-risk NMIBC at any assessment. If NMIBC was present at any assessment, patients discontinued treatment and entered survival follow-up. The primary endpoint was a CR, defined as absence of NMIBC (and disease-free survival in cohort B).

The interim analysis used an enrollment cutoff to ensure adequate follow-up for response evaluation. The database cutoff was July 18, 2018 and the enrollment cutoff was April 1, 2018.

The outcomes presented were from 103 of the 130 patients in cohort A, in 32 of whom treatment is ongoing. The median follow-up in this cohort was 14.0 months. The reason for discontinuation from the cohort included persistent disease in 32 patients, recurrent disease in 27 patients, adverse events (AEs) in 7 (of which 5 were drug related), physician decision in 3, protocol violation in 1, and patient withdrawal in 1.

All 103 cohort A patients had urothelial cell carcinoma as their histology. Tumor pattern was CIS with T1 in 13 patients, CIS with high-grade Ta in 16, and CIS alone in 74. Median patient age was 73 years. Patients had a median of 12 prior BCG instillations. Thirty-nine patients had a PD-L1 combined positivity score (CPS) ≥10 and 59 had a CPS <10.

At month 3, 38.8% (n = 40) had a CR. The median time to CR was 12.4 weeks (95% CI, 10.4-19.3). Twenty-nine (72.5%) responders had ongoing responses. The median duration of CR had not been reached. Some 80% of patients had a CR duration ≥6 months.

Some 55.3% (n = 57) of patients did not achieve CR. Of those, 45.6% (n = 47) had persistence, 8.7% (n = 9) had NMIBC stage progression, and 1.0% (n = 1) had visceral disease. No patient progressed to T2 tumor. Six patients were nonevaluable.

Almost all (96.1%) patients had at least 1 AE. The rate of grade 3/5 AEs was 26.2% and the rate of grade 3/5 treatment-related AEs was 12.6%. Three patients died, 2 unrelated to bladder cancer. Treatment-related AEs in ≥2 patients included pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), maculopapular rash (5.8%), arthralgia (4.9%), rash (4.9%), hyperthyroidism (3.9%), and nausea (3.9%).

The most common grade 3/5 treatment-related AEs were hyponatremia (2.9%) and arthralgia (1.9%). Immune-related grade 3/5 treatment-related AEs experienced by 1 patient each were adrenal insufficiency, colitis, hypophysitis, pruritus, rash, and type 1 diabetes.

Pembrolizumab currently has 2 approved indications in urothelial carcinoma: patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10), or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status; and patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

De Wit R, Kulkarni G, Uchio E, et al. Pembrolizumab for high-risk (HR) non—muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin (BCG): phase 2 KEYNOTE-057 trial. Presented at ESMO 2018; October 19-23, Munich, Germany. 864O.