A phase 1/2 trial of durvalumab plus intravesical gemcitabine and docetaxel in BCG-unresponsive non-muscle invasive bladder cancer patients (HCRN GU16-243: ADAPT-BLADDER Cohort 4).

667 Background: A critical need persists to develop treatments for BCG-unresponsive (BCG-U) non-muscle invasive bladder cancer (NMIBC) patients (pts). The intravesical gemcitabine plus docetaxel (Gem/Doc) doublet and intravenous agents targeting the PD-(L)1 immune checkpoint have both demonstrated complete responses (CRs) in BCG-U NMIBC investigations. With this knowledge, we aimed to assess the clinical efficacy and safety of durvalumab (D) in combination with intravesical Gem/Doc. Methods: The multi-arm, multi-stage ADAPT-BLADDER trial design has been previously described (Hahn NM et al, Eur Urol 2023). Here, we report outcomes from the D + Gem/Doc (cohort 4) phase 1 and phase 2 expansion arms. In phase 1, BCG-U NMIBC patients were enrolled in a 6 + 3 + 3 fashion to establish safety. In phase 2, additional patients were enrolled to evaluate the primary endpoint of CR rate in the total study population and to provide a CR rate estimate within the subset of patients with CIS. Per protocol, phase 1 and 2 efficacy analyses were combined. Enrollment of pure papillary patients was capped to ensure at least 20 patients with CIS. Patients received D 1500 mg iv on day 1 of each 4-week cycle for up to 6 cycles. In addition, they received intravesical Gem 1000 mg + Doc 37.5 mg weekly for the first 6 weeks. Patients achieving a CR were encouraged, but not required, to receive Gem/Doc monthly maintenance therapy. Cystoscopic and urine cytology assessments were performed every three months in year one with a mandatory biopsy at 12-months in responding patients. Toxicity rates were reported per CTCAE v5.0. Results: Between 1/2022-10/2024, 40 pts enrolled (12 phase 1, 28 phase 2) from 6 sites. The study completed its full planned accrual. Demographics included: median age 69 years; 83% male; CIS (8 pts), high-grade (HG) T1 + CIS (7 pts), HG Ta + CIS (6 pts), HG Ta (13 pts) and HG T1 (6 pts). No dose limiting toxicities were observed in the phase 1 portion. Among 27 patients (15 CIS, 12 papillary) evaluable for response at the August 2024 data lock, a CR was observed in 24 patients (89%) (CIS – 13/15 (87%); Papillary – 11/12 (92%)). Evaluation of pts still receiving study treatment for CR and durability of response is ongoing. One pt (4%) progressed to muscle invasion on study treatment. Highest grade treatment-related adverse events observed were grade 1 – 12 (36%) pts, grade 2 – 11 (33%) pts, grade 3 – 2 (6%) pts (sepsis n=1, pneumonitis n=1), and grade 4 – 1 (3%) pt (cough n=1) respectively. One on-study death due to retroperitoneal bleed unrelated to study therapy was observed. Conclusions: Combination treatment with durvalumab plus intravesical gemcitabine and docetaxel demonstrates promising clinical efficacy with a high complete response rate. Observed adverse event type, frequency, and severity were consistent with prior durvalumab trial experiences. Clinical trial information: NCT03317158 .