This is a multicenter, randomized controlled clinical trial (HOPE-07) designed to evaluate the efficacy and safety of perioperative treatment with disitamab vedotin (RC48) combined with toripalimab compared with toripalimab combined with chemotherapy in patients with resectable HER2-expressing (HER2 1+, 2+, or 3+) muscle-invasive bladder cancer (MIBC, cT2-4aN0/1M0).A total of 240 patients will be enrolled and randomized in a 1:1 ratio to receive either RC48 plus toripalimab or chemotherapy plus toripalimab, with 120 patients in each arm.
The primary objective is to compare 2-year event-free survival (2-year EFS) between the two treatment groups.
Secondary endpoints include pathological complete response (pCR), event-free survival (EFS), disease-free survival (DFS), 1-year event-free survival (1-year EFS), metastasis-free survival (MFS), overall survival (OS), R0 resection rate, and safety outcomes including adverse events (AEs), serious adverse events (SAEs), vital signs, physical examination, ECOG performance status, laboratory tests, and electrocardiography, assessed according to CTCAE v5.0.
Exploratory objectives include assessment of quality of life using EQ-5D-5L and EORTC QLQ-C30, evaluation of associations between biomarkers (HER2 expression, PD-L1 expression, circulating tumor DNA) and treatment efficacy, and multi-omics analyses using tumor tissue, ctDNA, and urinary tumor DNA to identify potential predictive biomarkers.
Willing and able to provide written informed consent and comply with study requirements and scheduled assessments.
Male or female patients aged ≥18 years at the time of signing informed consent.
Histologically or radiologically confirmed muscle-invasive bladder cancer (MIBC) staged as cT2-T4aN0/1M0 according to AJCC 8th edition, with residual disease after transurethral resection of bladder tumor (TURBT) as assessed by the investigator. All patients must have histological evidence of muscularis propria invasion. For mixed histology tumors, urothelial carcinoma must be the predominant component (≥50%).
HER2 expression ≥1+ confirmed by immunohistochemistry (IHC) testing of pretreatment tumor tissue in a local laboratory.
Prior treatment with therapies targeting PD-1, PD-L1, PD-L2, CTLA-4, HER2, or any other immune checkpoint or T-cell co-stimulatory pathways.
Receipt of any systemic anticancer therapy or systemic immunomodulatory agents (e.g., interferon, interleukin-2, tumor necrosis factor) within 28 days prior to enrollment.
Prior radiotherapy for bladder cancer.
Prior systemic antitumor therapy for bladder cancer (e.g., chemotherapy), except for intravesical chemotherapy or immunotherapy completed at least 2 weeks prior to initiation of study treatment.
Parallel
Disitamab Vedotin (RC48)
DrugDisitamab vedotin (RC48) will be administered in combination with toripalimab in the experimental arm. Treatment consists of 6 cycles in the neoadjuvant setting prior to radical cystectomy, followed by 6 cycles in the adjuvant setting after surgery. Toripalimab maintenance therapy will continue for up to 1 year in patients without disease progression or unacceptable toxicity.
Gemcitabine + Cisplatin（GC）+Toripalimab
DrugGemcitabine and cisplatin (GC) chemotherapy will be administered in combination with toripalimab in the control arm. Treatment consists of 4 cycles in the neoadjuvant setting prior to radical cystectomy.
Toripalimab (JS001 )
DrugToripalimab will be administered in combination with disitamab vedotin in the experimental arm during both neoadjuvant and adjuvant phases, and will be continued as maintenance therapy for up to 1 year after surgery in patients without disease progression or unacceptable toxicity.
Toripalimab (JS001 )
DrugToripalimab will be administered in combination with GC chemotherapy in the neoadjuvant setting for 4 cycles prior to radical cystectomy and will be continued as maintenance therapy for up to 1 year after surgery in patients without disease progression or unacceptable toxicity.
2-year Event-Free Survival
Event-free survival is defined as the time from randomization to disease progression, recurrence, metastasis, or death from any cause, whichever occurs firsth
Pathological Complete Response (pCR)
Pathological complete response is defined as the absence of residual viable tumor cells in the surgical specimen (ypT0N0) at radical cystectomy.
Disease-Free Survival (DFS)
Disease-free survival is defined as the time from radical cystectomy to tumor recurrence or death from any cause, whichever occurs first.
Event-Free Survival (EFS)
Event-free survival is defined as the time from randomization to disease progression, recurrence, metastasis, or death from any cause, whichever occurs first.
Metastasis-Free Survival (MFS)
Metastasis-free survival is defined as the time from randomization to distant metastasis or death from any cause.
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West China Hospital
Lead sponsor
RenJi Hospital
Collaborator
Tongji Hospital
Collaborator
The Second Affiliated Hospital of Kunming Medical University
Collaborator
Peking University First Hospital
Collaborator
The First Affiliated Hospital of Air Force Medicial University
Collaborator
The First Affiliated Hospital with Nanjing Medical University
Collaborator
First Affiliated Hospital Xi'an Jiaotong University
Collaborator
Tianjin Medical University Second Hospital
Collaborator
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