Treatment of recurrent non-muscle invasive bladder cancer with UGN-301 (zalifrelimab) alone and in combination: A phase 1 dose escalation study.

752 Background: High-grade (HG) and intermediate-risk (IR) non-muscle invasive bladder cancer (NMIBC) often recurs/progresses. UGN-301 is an intravesical anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody, zalifrelimab, in reverse thermal hydrogel (RTgel). This phase 1 study (NCT05375903) assessed safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of UGN-301 alone or combined with either a fixed dose of intravesical UGN-201 (imiquimod; toll-like receptor 7 agonist) or gemcitabine (gem) for recurrent NMIBC. Methods: Adults with recurrent NMIBC (IR low-grade Ta/T1 Arm A or HG Ta/T1 and/or carcinoma in situ CIS ± Ta/T1) were eligible if they underwent tumor resection/fulguration pre-study treatment. Patients had 6 once-weekly intravesical instillations, with optional maintenance doses at 6, 9, and 12 months for recurrence-free (RF) Ta/T1 patients and CIS patients with complete response (CR). Treatment arms were UGN-301 monotherapy (Arm A), UGN-201 (200 mg)/UGN-301 (Arm B), or gem (1000 mg)/UGN-301, with assessments every 3 months post-initiation. Adaptive Bayesian logistic regression modeling guided dose escalation/selection of RP2D. Data cut: 9/5/25. Results: 20 patients received UGN-301 monotherapy (100 mg n = 3, 300 mg n = 6, 500 mg n = 8, and 700 mg n = 3; Arm A), 11 received UGN-201/UGN-301 (300 mg n = 3, 500 mg n = 8; Arm B), and 10 received gem/UGN-301 (300 mg n = 3, 500 mg n = 7; Arm C). All but 1 (Arm A) completed 6 induction instillations. Arm A dose escalation reached maximum feasible dose. Treatment-emergent adverse events (TEAEs) occurred in 14 (70%), 9 (82%), and 7 (70%) patients in Arms A, B, and C, respectively. No dose-limiting toxicities or TEAEs leading to discontinuation arose. Zalifrelimab was detected in urine with comparable exposure duration across arms. Systemic zalifrelimab was detected in 2 patients (≥60-fold lower than intravenous administration). At UGN-301 doses ≥300 mg, 33.3% (2/6), 100% (3/3), and 33.3% (1/3) of CIS ± Ta/T1 patients had CR and 50% (5/10), 75% (6/8), and 71.4% (5/7) of Ta/T1 patients were RF at Week 12 when treated with UGN-301, UGN-201/UGN-301, or gem/UGN-301, respectively. Among those in Arm A who had CR or were RF at 3 months, 50% (1/2) of CIS ± Ta/T1 patients maintained CR up to 6 months and 60% (3/5) of Ta/T1 patients remained RF at 15 months. Likewise, 33.3% (1/3) of CIS ± Ta/T1 patients and 83.3% (5/6) of Ta/T1 patients in Arm B were free of disease through 9 months and are being followed. Conclusions: Intravesical UGN-301 in RTgel provided sustained bladder exposure to zalifrelimab with minimal systemic absorption, limiting CTLA-4-related toxicity. UGN-301 alone or with UGN-201 or gem showed favorable safety and preliminary efficacy, supporting further evaluation of 500 mg UGN-301. Assessment of response duration in combination arms is ongoing. Clinical trial information: NCT05375903 .