Phase 1/2 study of an anti-PD-L1/IL-15 variant fusion protein (SIM0237) in BCG-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC).

764 Background: Treatment options for BCG-unresponsive (UR) NMIBC are limited. Anti-PD-1 monotherapy and IL-15 agonist in combination with BCG have shown clinical efficacy in BCG-UR carcinoma in situ (CIS) NMIBC. It remains unclear whether targeting both PD-(L)1 and IL-15 has synergistic effect in NMIBC. SIM0237 is an anti-PD-L1/IL-15 variant fusion protein. The single agent showed good safety profile and promising efficacy signal in patients with BCG-UR NMIBC in the dose escalation part. This abstract reported data from the dose escalation and expansion parts of SIM0237 monotherapy from the ongoing Phase 1/2 study (NCT06186414). Methods: Patients with BCG-UR high-risk NMIBC received intravesical SIM0237 following the standard induction/maintenance treatment schedule. A re-induction course was allowed if the patients had persistent CIS or high-grade Ta at Month 3. Key study endpoints included DLT, safety, tolerability, PK and efficacy complete response (CR) rate and duration of CR for CIS NMIBC, disease-free survival (DFS) and DFS rate at specific time points for papillary-only NMIBC. Results: From January 10, 2024 to the data cutoff date of August 8, 2025, a total of 43 patients (10 CIS with or without Ta/T1, 33 papillary-only) have received SIM0237 monotherapy, with 3, 10 and 30 patients at the dose levels of 75 mg, 150 mg and 300 mg, respectively. The median age was 62 years, with 81% male. The median number of prior BCG doses was 13. Of the 7 CIS patients who had at least 1 post-baseline tumor assessment, 6 achieved a best response of CR and 5 were maintaining the CR status. In the 33 papillary-only patients, the median follow-up duration was 4.57 months. The median DFS was immature, with a 12-month DFS rate of 75.4% (95% CI, 48.9%-89.4%). TEAEs occurred in 38 (88.4%) patients and 23 (53.5%) patients had TRAEs. The majority of TRAEs were Grade 1/2 and limited in the urinary system. Nine (20.9%) patients had Grade 3 TEAEs and 1 (2.3%) had Grade 3 TRAEs. No Grade 4 or 5 TEAEs were reported. Four (9.3%) patients had SAEs and 1 had TRSAEs of urinary bladder haemorrhage and prostatic haemorrhage. Ten (23.3%) patients had dose interruptions due to TEAEs, and 4 (9.3%) had dose interruptions due to TRAEs. No DLT, immune-related AE or AE leading to SIM0237 discontinuation. PK data showed undetectable systemic exposure of SIM0237 in all 29 patients with serum samples analyzed. Conclusions: Intravesical SIM0237 was safe and well tolerated with promising clinical efficacy in patients with BCG-UR high-risk NMIBC. The Phase 3 study of SIM0237 monotherapy in this patient population is under plan. Clinical trial information: NCT06186414 .