Outcomes of patients with bacillus Calmette-Guérin–unresponsive high-risk non–muscle-invasive bladder cancer who demonstrated nonresponse to pembrolizumab in KEYNOTE-057: A post hoc analysis.

4597 Background: The phase 2 KEYNOTE-057 trial (NCT02625961) demonstrated that pembrolizumab can serve as a bladder-sparing option for patients (pts) with high-risk non–muscle-invasive bladder cancer (NMIBC) who are unresponsive to bacillus Calmette-Guérin (BCG) and are unable or unwilling to undergo radical cystectomy (RC). However, the outcomes (especially related to progressive disease PD) of pts who do not respond to bladder-sparing therapies (BSTs), including pembrolizumab, are of concern. We conducted a post hoc analysis of the KEYNOTE-057 trial to assess the clinical outcomes of pts who experienced persistent or recurrent high-risk NMIBC despite pembrolizumab therapy and subsequently received either RC or other BST. Methods: Pts with BCG-unresponsive carcinoma in situ (CIS) and/or papillary-only tumors who had nonresponse (persistent or recurrent high-risk NMIBC) to pembrolizumab were evaluated in the following groups: (1) pts who received upfront RC (≤4 mo of treatment failure confirmation); (2) pts who received delayed RC (>4 mo after treatment failure or received other BST before RC); and (3) pts who received BST alone (received BST alone or no reported subsequent treatment). Analyses included PFS (lack of development of muscle-invasive bladder cancer MIBC or metastatic disease or death due to PD) and OS, indexed from the date of pembrolizumab nonresponse. Pts with upfront RC found to have upstaging to MIBC (due to initial understaging) were excluded from the PFS analysis unless they developed subsequent PD. Pathologic outcomes in pts undergoing upfront vs delayed RC were also evaluated. Results: Of the 144 pts who were nonresponders to pembrolizumab, 39 underwent upfront RC, 33 underwent delayed RC, and 72 underwent BST alone. Of pts who underwent upfront RC, the pathologic stages were T0, 26%; NMIBC (Ta, T1, CIS), 64%; and MIBC (T2, T3, T4), 10%. Of pts who underwent delayed RC, the pathologic stages were T0, 15%; NMIBC, 67%; and MIBC, 15%. Median time from pembrolizumab nonresponse to data cutoffs (cohort A: May 30, 2023; cohort B: Oct 20, 2022) was 59.7 mo (range, 10.9-80.7). Median PFS was not reached across all 3 groups. The 36-mo PFS rates were 78% (95% CI, 60-89) for upfront RC, 68% (95% CI, 49-82) for delayed RC, and 86% (95% CI, 74-92) for BST alone. Median OS was not reached across all 3 groups. Conclusions: Oncologic outcomes were similar between pts treated with BST or RC following nonresponse to pembrolizumab. Pts who underwent upfront vs delayed RC had similar pathologic outcomes. Data from this analysis suggest that pts were not harmed by BST following pembrolizumab and that a window of safety may exist for implementing second-line BST prior to RC. Clinical trial information: NCT02625961 .