Phase 2 trial of pembrolizumab (P) with response-guided bladder-sparing in patients with muscle-invasive bladder cancer (MIBC; HCRN GU 20-444).

Many pts with MIBC are not candidates for radical cystectomy (RC) and/or favor bladder-sparing alternatives. Neoadjuvant chemotherapy (NAC) following TURBT leads to a pathologic complete response (pCR) in a subset of pts, suggesting that RC is not universally required to achieve cure. We previously showed that TURBT followed by cisplatin-based NAC plus PD-1 blockade yielded a stringently defined clinical CR (cCR) in 43% of pts and ~2/3 of such pts omitting upfront RC experienced durable bladder-intact survival (Galsky, Nat Med, 2023). However, ~50% of pts with MIBC are ineligible for cisplatin, and neoadjuvant PD-1 blockade monotherapy can produce pCR rates of 30-40%. HCRN GU 20-444 evaluated TURBT followed by P monotherapy with response-guided bladder-sparing for pts with MIBC. Methods: Eligible pts had cT2-3N0M0 urothelial cancer and were cisplatin-declining or -ineligible. Following maximal TURBT, pts received 2 cycles of P (q6 week dosing) followed by clinical restaging with MRI/CT, urine cytology, and cystoscopy with biopsies. Pts with a cCR omitted definitive local therapy and received up to 7 additional cycles of P. Pts without a cCR received definitive local therapy (RC or chemoradiation). ctDNA was serially evaluated through WGS of tumor and plasma coupled with artificial intelligence-based pattern recognition for ultrasensitive detection of residual disease (TrueMRD, Veracyte). The primary endpoint was cCR rate. Key secondary and exploratory endpoints included 2-year MFS, OS, and ctDNA status. Results: From 7/2022 to 12/2024, 46 pts were enrolled; the median age was 74 (24% were ≥80). cCR was achieved in 43% (95% CI 29%-59%) of pts. Median follow-up was 11 months (range 2.4-33.5). Among pts achieving a cCR, all proceeded without upfront RC, none developed metastatic disease; 1/20 had a delayed cystoprostatectomy due to a new prostate cancer (bladder cancer pT0N0); 2/20 died due to non-cancer causes. Adverse events were consistent with the toxicity profile of P. Cycle 1 (C1) ctDNA was undetectable in 90% and 55% of pts with and without a cCR, respectively (Mann-Whitney P = 0.01). Undetectable C1 ctDNA was associated with improved MFS (HR 11.2, 95% CI 2.2-57, log-rank P = 0.0003) and OS (HR 11.4, 95% CI 1.3-103, P = 0.007). C2 ctDNA was undetectable in 100% pts with a cCR. Among pts without a cCR, undetectable C2 ctDNA was associated with improved MFS (HR 14.8, 95% CI 1.4-2000, P = 0.02). Conclusions: TURBT plus P monotherapy yields promising bladder-intact metastasis-free survival in pts achieving a stringently defined cCR. Pts with C1 or C2 undetectable ctDNA have an extremely low risk of metastatic recurrence, even when omitting RC. ctDNA status after only 6 weeks of P distinguishes outcomes in pts without a cCR. These findings highlight the potential of cCR status coupled with ctDNA to redefine response-guided individualized treatment pathways in MIBC. Clinical trial information: NCT05406713.