Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.

person Junru Chen West China Hospital of Sichuan Univertity, Chendu, China info_outline Junru Chen, Haoyang Liu, Qiyu Zhu, Chenhao Xu, Qiang Wei, Jiyan Liu, Zhenhua Liu, Pengfei Shen, Yige Bao, Peng Zhang, Banghua Liao, Jin Yao, Ni Chen, Kaijie Wu, Xiaodong Liu, Hao Zeng

Authors person Junru Chen West China Hospital of Sichuan Univertity, Chendu, China info_outline Junru Chen, Haoyang Liu, Qiyu Zhu, Chenhao Xu, Qiang Wei, Jiyan Liu, Zhenhua Liu, Pengfei Shen, Yige Bao, Peng Zhang, Banghua Liao, Jin Yao, Ni Chen, Kaijie Wu, Xiaodong Liu, Hao Zeng Organizations West China Hospital of Sichuan Univertity, Chendu, China, West China Hospital, Sichuan University, Chengdu, Sichuan, China, Department of Urology, West China Hospital, Sichuan University, Chengdu, China, West China Hospital, Sichuan University, Chengdu, China, Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China, Department of Radiology, West China Hospital, Sichuan University, Chengdu, China, Department of Pathology, West China Hospital, Sichuan University, Chengdu, China, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xian, China, The First Affiliated Hospital of Kunming Medical University, Kunming, China Abstract Disclosures Research Funding No funding sources reported Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952.

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