Background: The majority of pts presenting with bladder cancer ( > 70,000 cases/y in the United States) have NMIBC. Despite standard of care therapy with transurethral resection of bladder tumor [TURBT] and BCG administration, a large percentage of pts will have disease recurrence/progression. PD-L1 is widely expressed in urothelial tumors. Pembrolizumab, an anti–PD-1 antibody, blocks the interaction of PD-1 and its ligands, PD-L1 and PD-L2. KEYNOTE-057 (NCT02625961) is a single-arm, open-label, phase 2 study to evaluate pembrolizumab in pts with high-risk NMIBC unresponsive to BCG. Methods: Key inclusion criteria include age ≥ 18 y; BCG-unresponsive NMIBC (high-grade Ta, T1, and/or carcinoma in situ [CIS] despite adequate BCG treatment); ineligible for/or declines radical cystectomy; ECOG PS 0-2. Pts must have undergone ≥ 2 cystoscopic procedures with the most recent ≤ 8 wk of study start, including complete TURBT (tissue sample must be available). Pts will receive pembrolizumab 200 mg Q3W for 24 mo or until disease recurrence or progression, unacceptable toxicity, pt withdrawal, or investigator decision. Pts will be placed into cohorts by presence (cohort A) or absence (cohort B) of CIS based on tissue pathology at screening. Tumors will be evaluated using cystoscopy and urine cytology every 12 wk for the first 2 y, every 24 wks for the next 2 y, and every 52 wk thereafter. CT imaging will be used to assess for upper tract and metastatic or nodal disease. At 18 mo, pts with no evidence of disease may discontinue treatment. Pts with low-grade Ta recurrence will be allowed to undergo repeat TURBT and remain on treatment; low-grade recurrence will not be considered treatment failure. AEs will be monitored throughout the study and for 30 days (90 days for SAEs and ECIs) after study end and graded per CTCAE v4.0. The primary end points are complete response for pts with CIS (cohort A) and disease-free survival for those without CIS (cohort B); secondary end points include progression-free survival, overall survival, duration of response, and PD-L1 expression in relation to clinical outcome. Enrollment is ongoing and will continue until ~260 pts are enrolled. Clinical trial information: NCT02625961