Background: Pembrolizumab (pembro) was approved in January 2020 for treatment of HR NMIBC based on interim results from 96 patients (pts) in the open-label, single-arm, multicenter, phase II KEYNOTE-057 (NCT02625961) study. Here we present updated efficacy and safety results with extended minimum follow-up of 26.3 mo from KEYNOTE-057 cohort A. Methods: Pts aged ≥18 years with histologically confirmed Bacillus Calmette-Guérin (BCG)–unresponsive HR carcinoma in situ (CIS), with or without papillary tumors, who were ineligible for or declined radical cystectomy (RC) received pembro 200 mg Q3W for up to 24 mo or until disease persistence, recurrence, progression, or unacceptable toxicity. Primary end point: complete response rate (CRR). Key secondary end points: duration of response (DOR) and safety. Results: Overall, 101 pts received pembro and 96 were included in the efficacy analysis (5 patients did not meet BCG-unresponsive criteria). Median age was 73 years (range, 44-92), and pts received a median of 12.0 (range, 7.0-45.0) BCG instillations. Median time from enrollment to data cutoff date of May 25, 2020, was 36.4 mo (range, 26.3-48.5). Of 96 pts, CRR was 40.6% (95% CI, 30.7-51.1) at first evaluable disease assessment, and median DOR was 16.2 mo (range, 0.0+ to 36.2). Of 39 responders, 13 (33.3%) remained in CR ≥18 mo and 9 (23.1%) remained in CR ≥24 mo as of the data cutoff date. No pt progressed to MIBC while on study treatment based on protocol-specified disease assessments. CRR was generally consistent with the primary analysis across protocol-prespecified subgroups, including PD-L1 expression status. Forty pts (41.7%) underwent RC after discontinuation of pembro; 35 pts (88%) had no pathologic upstaging to MIBC, 2 (5%) had no available pathology data, and 3 (8%) had evidence of MIBC (all nonresponders); 1 pt had pT2N0 disease at 60 days after the last pembro dose, 1 pt had pT2N1 disease (involvement of a single perivesical lymph node) at 86 days after the last pembro dose, and 1 pt had pT3N1 disease at 457 days after the last pembro dose. For other subsequent treatments, 30 of 96 pts (31.3%) received additional intravesical therapy (eg, BCG), 27 of 96 (28.1%) underwent local procedures (eg, TURBT), and 10 of 96 (10.4%) received systemic therapy. In 101 pts, treatment-related AEs (TRAEs) occurred in 67 pts (66.3%); most frequent were diarrhea, fatigue, and pruritus (10.9% each). Grade 3/4 TRAEs occurred in 13 pts (12.9%). Twenty-two pts (21.8%) experienced immune-related AEs; 3.0% were grade 3-4. Seven pts (6.9%) discontinued due to TRAEs. There were no grade 5 TRAEs. Conclusions: With extended follow-up, pembro continued to show durable and clinically meaningful activity in pts who had HR BCG-unresponsive CIS with or without papillary tumors and who were ineligible for or declined RC. No new safety risks were identified. Clinical trial information: NCT02625961