Formula-01: A phase Ⅱ study of disitamab vedotin (RC48) intravenous injection combined with BCG intravesical instillation in high-risk non-muscle invasive bladder cancer with HER2 high expression.

TPS894 Background: Intravesical instillation of bacillus Calmette-Guérin (BCG) is the first-choice treatment for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). However, our previous study has demonstrated that HER2 was an independent predictor of poor BCG efficacy in NMIBC (Tan et al., European Urology Oncology, 2023). We found that high-risk NMIBC patients with HER2 high expression had the highest risk of disease recurrence and progression with 46.9% 2yr-RFS rate and 23.0% 2yr-PFS rate. Disitamab Vedotin (RC48) is an antibody-drugconjugate(ADC) targeting HER2 with a payload of MMAE. Formula-01 will evaluate the efficacy and safety of RC48 combining with BCG instillation in HER2 overexpression high-risk NMIBC patients. Methods: Formula-01 is an open-label, non-randomized, phase 2 trial. Patients must receive complete transurethral resection (TURBT) of bladder tumor (R0 resection) and did not accept BCG intravesical instillation and neoadjuvant chemotherapy or radiotherapy before. NMIBC was pathologically confirmed for all patients according to the 8th edition of the TNM staging system and the risk stratification was recorded basing on the American Urological Association (AUA)/Society of Urologic Oncology (SUO) guidelines.The pathology of NMIBC must be pure urothelial carcinoma and any divergent differentiation subtypes are excluded. This study is open at the Sun Yat-sen University Cancer Center (SYSUCC) and 70 patients are enrolled. The single-arm cohort will receive RC48 intravenous injection (2.0 mg/kg, iv drip, d1, Q2W, 8 cycles) combining with BCG intravesical instillation at least one year (D2PB302 strain, 1.2×10 8 CFU, 120 mg, dissolved in 40–50 ml of saline, 19 times in 1 yr). The primary endpoint is 2yr-RFS rate. Secondary endpoints include 1yr-RFS, 1yr-PFS, 2yr-PFS rate, bladder retention rate and safety. Exploratory analyses include determination of Her2 expression, molecular subtypes. The sample size calculation is based on the historical results of specific subgroup patients with 2yr-RFS rate of 46.9%, and we expected improvements to 70.0%. One-sample long-rank test was used to calculate the enrollment of 70 patients (α=0.05, β=0.8, lost-to-follow-up rate of 5.0%). The study began enrollment in February, 2024 and completed enrollment in October, 2024. Research approval was obtained from the SYSUCC Ethics Committee. Clinical trial information: ChiCTR2400080767 .