HOPE-07-MIBC: Disitamab Vedotin Plus Immunotherapy vs Chemoimmunotherapy in Resectable HER2-Expressing MIBC

A Prospective, Randomized Controlled Study of Perioperative Disitamab Vedotin Plus Immunotherapy Versus Chemotherapy Plus Immunotherapy in Patients With Resectable HER2-Expressing Muscle-Invasive Bladder Cancer (HOPE-07-MIBC Study)

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.

Inclusion Criteria:

1. Willing and able to provide written informed consent and comply with study requirements and scheduled assessments.

2. Male or female patients aged ≥18 years at the time of signing informed consent.

3. 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%).

4. HER2 expression ≥1+ confirmed by immunohistochemistry (IHC) testing of pretreatment tumor tissue in a local laboratory.

5. Deemed suitable for radical cystectomy as assessed by the investigator.

6. No prior systemic chemotherapy or immunotherapy for muscle-invasive bladder cancer.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

8. Adequate organ function as defined by the following laboratory criteria obtained within 14 days prior to enrollment (unless otherwise specified):

   Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L Platelet count ≥100 × 10⁹/L Hemoglobin ≥90 g/L International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤1.5 × upper limit of normal (ULN) Total bilirubin ≤1.5 × ULN AST, ALT, and alkaline phosphatase ≤2.5 × ULN Creatinine clearance (CrCl) >40 mL/min Left ventricular ejection fraction (LVEF) ≥50% For borderline renal function: CrCl ≥40 to <60 mL/min (defined subgroup); adequate renal function: CrCl ≥60 mL/min

9. Women of childbearing potential must agree to use highly effective contraception during the study and for at least 180 days after the last dose of disitamab vedotin or toripalimab (whichever occurs later). A negative urine or serum pregnancy test is required within 7 days prior to enrollment.

10. Non-sterilized male patients must agree to use highly effective contraception during the study and for at least 180 days after the last dose of disitamab vedotin or toripalimab (whichever occurs later).

11. Life expectancy of more than 12 months.

12. Willing and able to comply with study procedures and follow-up visits.

Exclusion Criteria:

1. 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.
2. Receipt of any systemic anticancer therapy or systemic immunomodulatory agents (e.g., interferon, interleukin-2, tumor necrosis factor) within 28 days prior to enrollment.
3. Prior radiotherapy for bladder cancer.
4. 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.
5. Major surgery or significant traumatic injury within 28 days prior to enrollment. Placement of vascular access devices and transurethral resection of bladder tumor (TURBT) are not considered major surgery.
6. Severe infections requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days prior to enrollment (hepatitis B virus infection is addressed in exclusion criterion 12).
7. Receipt of live vaccines within 28 days prior to enrollment (inactivated influenza vaccines are allowed; intranasal vaccines are considered live vaccines and are not allowed).
8. Use of traditional Chinese medicine or proprietary Chinese medicine with anti-cancer intent within 14 days prior to enrollment.
9. Active autoimmune disease requiring systemic treatment that may interfere with study therapy as judged by the investigator.
10. Requirement for long-term systemic corticosteroids or other immunosuppressive therapy that may interfere with study treatment.
11. Any uncontrolled comorbid conditions that may affect study participation, including but not limited to significant electrolyte abnormalities, hypoalbuminemia, interstitial lung disease, non-infectious pneumonitis, uncontrolled tuberculosis, neurological disorders, psychiatric disorders, or uncontrolled systemic diseases. This includes uncontrolled cardiovascular disease such as active cardiac disease within 6 months prior to enrollment, including severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, or clinically significant arrhythmias requiring treatment.
12. Chronic hepatitis B infection with HBV DNA ≥500 IU/mL (2500 copies/mL) without adequate antiviral therapy. Patients with inactive HBsAg carrier status or well-controlled HBV infection (HBV DNA <500 IU/mL under antiviral therapy) may be eligible. HBV DNA testing is required only in HBsAg-positive patients.
13. Active hepatitis C infection. Patients who are HCV antibody negative, or HCV antibody positive with negative HCV RNA, are eligible. HCV RNA testing is required for HCV antibody-positive patients.
14. History of immunodeficiency, including HIV infection, other acquired or congenital immunodeficiency disorders, or prior allogeneic stem cell transplantation or solid organ transplantation.
15. Known hypersensitivity to any study drug, its excipients, or other monoclonal antibodies.
16. Pregnant or breastfeeding women.
17. Concurrent participation in another interventional clinical trial.
18. Presence of another active malignancy, except for adequately treated non-melanoma skin cancer or other malignancies considered cured.
19. Any condition that, in the investigator's judgment, makes the patient unsuitable for participation in the study