Multi-Omics-Based Phase Ⅱ Trial of Trastuzumab Rezetecan Plus Camrelizumab for Perioperative Therapy in HER2-Positive Muscle-Invasive Urothelial Carcinoma

Phase Ⅱ Clinical Study on Predicting Perioperative Efficacy of Trastuzumab Rezetecan Combined With Camrelizumab in HER2-Positive Muscle-Invasive Urothelial Carcinoma Based on Multi-Omics

For patients with HER2-expressing muscle-invasive bladder cancer (MIBC), current neoadjuvant therapies dominated by platinum-based chemotherapy remain unsatisfactory with respect to improved clinical efficacy, pathological complete response (pCR) rates, and the achievement rate of tumor downstaging for bladder preservation; in addition, a subset of patients have limited tolerance or eligibility to chemotherapy. Therefore, this study aims to evaluate the neoadjuvant regimen of Ruikang Trastuzumab combined with Camrelizumab, to determine whether this regimen can, with acceptable safety profiles: elevate pCR rate and the proportion of patients downstaged to ≤T1 disease, enable bladder preservation based on TURBT for eligible patients, and explore predictive biomarkers to identify the population most likely to derive clinical benefits.

Inclusion Criteria:

1. Aged ≥18 years old with no restriction on gender.

2. Voluntarily participate in this trial, sign written informed consent form and have good treatment compliance.

3. Histopathologically confirmed bladder urothelial carcinoma (carcinoma with squamous/glandular differentiation is acceptable only when urothelial component dominates the lesion).

4. Clinically or radiologically diagnosed muscle-invasive bladder cancer (MIBC): cT2-T4a, N0-1, M0 per AJCC/UICC staging system; all imaging assessments shall be completed within 28 days prior to enrollment.

5. HER2-positive tumor defined as IHC 1+, 2+ or 3+ tested on archival tumor specimen before enrollment via designated or central laboratory.

6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

7. Candidates eligible for radical surgery: planned to receive radical cystectomy (RC), and investigators confirm feasibility of subsequent TURBT consistent with study protocol.

8. Satisfactory major organ function to tolerate perioperative treatment:

   • Hematology: ANC ≥1.5×10⁹/L, PLT ≥100×10⁹/L, Hb ≥90 g/L;
   • Liver function: ALT/AST ≤2.5×ULN, total bilirubin ≤1.5×ULN;
   • Renal function: creatinine clearance ≥50 mL/min calculated by Cockcroft-Gault or MDRD formula;
   • Cardiac function: LVEF ≥50% detected by echocardiography without symptomatic heart failure (due to trastuzumab-related cardiac risk).

9. Fertile subjects agree to use effective contraception throughout study period and for defined duration after last study drug administration.

Exclusion Criteria:

1. Patients with distant metastasis (M1), unresectable disease ineligible for radical surgery, or concomitant active malignancy requiring systematic anti-tumor therapy as assessed by investigator.
2. Prior systemic anti-tumor therapy for current bladder cancer, including neoadjuvant/adjuvant/metastatic chemotherapy, immunotherapy or anti-HER2 agents; previous exposure to PD-1/PD-L1 inhibitors, anti-HER2 monoclonal antibodies or ADCs that may interfere with efficacy or safety evaluation per investigator's judgment.
3. Previous pelvic radiotherapy, or unrecovered major surgery/severe trauma within predefined time window before enrollment.
4. Active autoimmune disease or patients requiring long-term systemic immunosuppressive therapy (daily prednisone>10 mg or equivalent dose; topical/inhaled/short-course steroid use is permitted).
5. Uncontrolled active or severe bacterial infection, active tuberculosis; viral infection: HBsAg positive with elevated HBV DNA without standardized antiviral treatment, positive HCV RNA without disease control, or confirmed HIV infection per local institutional standard; clinically significant cardiovascular disorders including congestive heart failure, recent myocardial infarction, unstable angina, uncontrolled arrhythmia, baseline LVEF<50%, or subjects inappropriate for trastuzumab administration judged by investigator.
6. Previous or ongoing interstitial lung disease/non-infectious pneumonitis, or obvious interstitial pulmonary changes on imaging with high risk of immune-related pneumonitis assessed by investigator.
7. Known severe hypersensitivity to trastuzumab, camrelizumab or any excipients of investigational drugs; pregnant or breastfeeding females, or those planning pregnancy throughout study period.
8. Severe psychiatric/cognitive disorder or substance abuse preventing regular follow-up and efficacy assessment.
9. Any other conditions inappropriate for trial enrollment such as severe comorbidities or extremely short expected survival, as determined by the investigator.