This study is an open-label, single-arm investigator-initiated clinical trial, aiming to evaluate the efficacy and safety of vicedetinib bladder instillation combined with teprotumumab in the treatment of patients with HER2-expressing, previously untreated, or BCG-resistant high-risk non-muscle-invasive bladder cancer (NMIBC). The subjects to be included in the study must have undergone standard TURBT within 3 weeks before enrollment, removed all visible lesions, and had a clear pathological diagnosis of NMIBC, with their risk classification according to the "Chinese Bladder Cancer Diagnosis and Treatment Guidelines (2022)" falling into the high-risk group (including extremely high-risk group). All surgical tumor specimens of the included subjects underwent HER2 testing, indicating HER2 expression, defined as immunohistochemistry (IHC) 1+, 2+ or 3+, with FISH verification for amplification if IHC 2+ is present. The subjects were divided into two groups based on whether they had received BCG treatment in the past: one group was high-risk NMIBC patients who had not received BCG treatment, including one of the following situations: ① refused BCG treatment, ② had contraindications to BCG use, ③ BCG was inaccessible; the other group was high-risk NMIBC patients who had no response to BCG, meeting any of the following criteria: ① had persistent/recurrent high-risk NMIBC within 12 months (±1 month) after adequate BCG treatment, ② had high-grade T1 disease during the first assessment after induction BCG treatment. Adequate BCG treatment was defined as completing at least 5 BCG bladder instillations within 2 months, and then at least 2 BCG bladder instillations for 6 consecutive weeks within the next 10 months, meaning at least "5+2" BCG bladder instillations within approximately 12 months. Eligible subjects received vicedetinib bladder instillation combined with teprotumumab treatment; vicedetinib was administered once weekly at 180mg for 8 times. For patients receiving treatment, if there was no occurrence of persistent/recurrent NMIBC, disease progression, or intolerable toxicity, they would receive maintenance bladder instillation with vicedetinib for one year, with the maintenance regimen being: once every 4 weeks for 10 times. Teprotumumab: 240mg per dose, intravenous, once every 3 weeks for 1 year. Patients were required to collect urine samples before the first treatment and after the last treatment. Safety during the study was evaluated according to the NCI-CTCAE V5.0 standard, and the observation indicators included vital signs, physical examination, laboratory tests, electrocardiogram and echocardiogram examinations, adverse events and serious adverse events.
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Within 3 weeks after TURBT surgery, the tumor tissue specimens obtained from the subjects were subjected to immunohistochemical (IHC) testing for HER2 expression, which met the criteria of 1+, 2+ or 3+. If the IHC result was 2+, FISH verification for amplification was required.
ECOG physical condition: 0 - 2 points.
Sufficient heart, bone marrow, liver and kidney functions should meet the following standards within 7 days before the drug administration study (normal values are based on the clinical trial center): Left ventricular ejection fraction ≥ 50%; Hemoglobin ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; Platelets ≥ 100 × 10^9/L; Serum total bilirubin ≤ 1.5 times the upper limit of normal value (ULN); ALT and AST ≤ 2.5 × ULN; Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance rate (CrCl) ≥ 50 mL/min according to the Cockcroft-Gault formula.
Muscle-invasive bladder cancer (T2 and above) and/or those with regional lymph node and distant metastasis.
Combined urinary tract urothelial carcinoma outside the bladder (i.e., in the urethra, ureters or renal pelvis).
The study excluded any patients who had received any other anti-tumor treatments within 4 weeks prior to the administration of the drug, such as chemotherapy, radiotherapy, targeted therapy, immunotherapy, etc. This exclusion did not include the one-time perfusion chemotherapy immediately performed after TURBT.
Before the start of the drug study, there was no recovery from the adverse events caused by the previously used anti-tumor drugs to the 0-1 level of CECAT within 2 weeks.
Single group
Intravesical Instillation of Disitamab Vedotin Combined with Toripalimab
DrugEligible subjects will be enrolled and treated with intravesical instillation of disitamab vedotin combined with toripalimab. Disitamab vedotin will be administered at a dose of 180 mg once weekly for 8 consecutive cycles. For treated patients without persistent/recurrent NMIBC, disease progression, or intolerable toxicity, maintenance intravesical instillation of disitamab vedotin will be performed within 1 year. The regimen for maintenance therapy is 180 mg once every 4 weeks for 10 consecutive cycles. Toripalimab will be administered intravenously at a dose of 240 mg once every 3 weeks for 1 consecutive year.
The one-year recurrence-free survival rate of patients with high-risk NMIBC
After all subjects have been enrolled and followed up for an additional 12 months, or upon achievement of the required number of positive events, Recurrence-Free Survival (RFS) will be analyzed using the Kaplan-Meier method. The median recurrence-free time will be estimated via the Kaplan-Meier method. Hazard ratios (HR) and their 95% confidence intervals will be calculated using the Cox proportional hazards model.
The clinical complete remission rates for 3 months and 6 months
the proportion of patients achieving clinical complete remission at 3 months and 6 months.
Overall survival period
Overall Survival (OS) is defined as the time from the date of initial treatment to death from any cause. Patients who remain alive at the last follow-up will be censored.
Progression-free survival time
Progression-free survival (PFS) is defined as the time from the initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever comes first.
Adverse event
An adverse event (AE) is any unfavorable or unintended medical occurrence in a subject administered a study drug, which does not necessarily have a causal relationship with the study treatment.
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