A multi-center phase Ib/II study of RC48-ADC combined with tislelizumab as neoadjuvant treatment in patients with HER2 positive locally advanced muscle-invasive urothelial bladder cancer (Hope-03).
Authors: Wen Feng , Lin Tianhai , Tan Ping , Deng Jiani , Ren Min , Zhang Mengni , Zheng Xiaonan , Zhang Peng , Shen Yali 
Published: February 2025

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Background:
To evaluate the safety and efficacy of RC48-ADC, a humanized anti-HER2 antibody conjugated with monomethyl auristatin E, and tislelizumab, a PD-1 antibody, as a novel neoadjuvant treatment combination in patients with HER2 positive locally advanced muscle-invasive bladder cancer (MIBC). The study design has been presented at 2022 ESMO Asia meeting, and preliminary results will be reported this time.
Methods:
This is a Ib/II, multi-center, open-label, single-arm study (ChiECRCT20210564). Patients with pathological and imaging diagnosed cT2-4bN0-3M0-1a HER2 positive (Immunohistochemistry status 3+ or 2+ or 1+) MIBC. Of them, 6 patients are enrolled in the dose-escalation phase, and 45 patients enter into phase II study. RC48-ADC is given every 2 weeks with a maximum dose of 120mg intravenously, and tislelizumab is given every three weeks at the dose of 200mg intravenously. Patients without disease progression will receive radical cystectomy or bladder-sparing therapies based on individual risk profiles and preferences. The primary endpoints are clinical complete remission rate (cCR, T0/Ta/Tis), pathological complete remission rate (pCR) and safety.
Results:
Inclusion has been closed, with a total of 51 patients successfully enrolled, consisting of 7 females and 44 males. The median age was 70 ± 10.16 years. Among the participants, 3 patients were HER2(1+), 26 patients were HER2(2+), and 22 patients were HER2(3+). The median follow-up duration was 12.8 ± 1.81 months. A total of 46 patients underwent primary efficacy evaluation after neoadjuvant treatment: 26 patients cCR, 14 patients partial response (PR), 2 patients stable disease (SD), and 4 patients disease progression. The cCR rate was 56.52%, and the disease control rate (DCR) was 91.30%. Of the 51 patients, 36 opted for radiotherapy as bladder-sparing therapy, resulting in 1 patient achieving Tis and 35 achieving T0 after radiotherapy. Three patients have passed away so far, and the 18-month survival rate was 100%. Regarding safety, 7 patients experienced immune-related adverse events, including grade 2 myositis, grade 1 elevated transaminase, and grade 1 hyperthyroidism, which led to an interruption of tislelizumab treatment. Additionally, 10 patients experienced RC48-ADC-related toxicities, including grade 1 elevated transaminase, grade 2 erythema, and grade 2 paresthesia. Two treatment-related interruptions occurred.
Conclusions:
The novel neoadjuvant combination of RC48-ADC and tislelizumab demonstrated promising downstaging efficacy in patients with HER2-positive locally advanced MIBC and provides an opportunity for radiotherapy-based bladder-sparing treatment. The toxicities observed were manageable, and the long-term efficacy of bladder preservation will be confirmed in the final analysis. Clinical trial information: ChiECRCT20210564.