KEYNOTE-057

Background

Single-arm, open-label phase 2 trial (Cohort A). 148 patients with BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without high-grade papillary tumors, who were ineligible for or refused radical cystectomy. BCG-unresponsive defined per FDA guidance: persistent or recurrent high-grade disease after adequate BCG therapy. This cohort tested pembrolizumab as a bladder-preserving systemic option.

Interventions and follow up

Arm A: Pembrolizumab 200mg IV q3wk × up to 35 cycles
Arm B: Not applicable — single-arm study
Primary endpoint: Complete response rate (CR) at 3 months
mFollow up: 36.4 mo (updated analysis)

Results

CR rate at 3 months: 41.2%
Duration of CR ≥12 months: 46% of responders
mDuration of CR: 16.2 mo
24-mo cystectomy-free survival: ~43%

Adverse events

Overall grade ≥3: 13.5%
Immune-mediated (any grade): 20.3%
Endocrine: hypothyroidism (any grade) 10.8%
GI: colitis grade ≥3 2.7%
Pulmonary: pneumonitis grade ≥3 0.7%
Discontinuation due to AEs: 8.1%; most AEs immune-mediated and manageable with standard protocols

Conclusions

Pembrolizumab achieved a 41% CR rate in BCG-unresponsive CIS NMIBC in patients who could not or would not undergo cystectomy, with approximately half of responders maintaining response for ≥12 months. This provides a meaningful systemic option in a setting where radical cystectomy is the alternative and bladder preservation is a priority.

Key Limitations

Key Limitations: Non-randomized single-arm design — no comparison to cystectomy, intravesical agents, or other options. The ~40% CR rate means the majority of patients do not respond and may face progressive disease with delayed cystectomy. Durability of response is limited: median duration of CR was 16 months. PD-L1 expression was not predictive of response in this cohort. The population excluded cystectomy-eligible patients who refused surgery — a self-selected group with potential survivorship bias. Surveillance cystoscopy and pathology adherence are critical to safe bladder-preserving management.

Clinical Context

FDA approved pembrolizumab for BCG-unresponsive NMIBC with CIS in 2020, based on KEYNOTE-057 Cohort A. It is one of few systemic options in this space where cystectomy remains the definitive standard. KEYNOTE-057 Cohort B (high-grade Ta without CIS) showed a lower CR rate (~46% for ≥3 months). Newer agents in BCG-unresponsive NMIBC include nadofaragene firadenovec (oncolytic adenovirus) and cretostimogene (gene therapy), broadening the bladder-preservation armamentarium.

References

References: Balar AV et al, Lancet Oncol 2021