A Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin Combined With PD-1 Inhibitor and Radiotherapy as Bladder-preserving Therapy in Patients With Localized HER2-high Expressing Muscle-invasive Bladder Urothelial Carcinoma Following Maximal Transurethral Resection

A Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin Combined With PD-1 Inhibitor and Radiotherapy as Bladder-preserving Therapy in Patients With Localized HER2-high Expressing Muscle-invasive Bladder Urothelial Carcinoma Following Maximal Transurethral Resection

This is a prospective, open label, multicenter clinical study of vediximab combined with PD-1 and radiation therapy for bladder preservation in MIBC patients with HER-2 high expression (IHC 2+or 3+), conducted in accordance with Good Clinical Practice (GCP).

Each patient received treatment with Vediximab injection [2.0 mg/kg, Q2W, iv] and Triprolizumab injection [3mg/kg, Q2W, iv] for one cycle, followed by concurrent radiotherapy in the second cycle. Assuming a 20% improvement in the efficacy of conventional TMT bladder protection treatment, i.e. an increase in CR rate from 60% to 80%, alpha of 0.05, and beta of 0.2, a sample size of 36 is required. Considering a 20% dropout rate, 45 subjects need to be enrolled.

The subjects need to undergo maximum transurethral resection of the bladder (TURBT) and imaging diagnosis, and collect urine samples before treatment. The researchers judged that localized myometrial invasive bladder cancer with high HER2 expression could be treated with bladder conserving therapy by maximizing TURBT. The patient will receive treatment with vediximab combined with PD-1 and radiotherapy after TURBT surgery (without the need for secondary resection).

The subjects should receive treatment with vediximab combined with PD-1 every two weeks for a total of 12 treatment cycles, and receive radiation therapy simultaneously. The specific number of treatment cycles will be determined by the researchers based on the patient's response to the treatment, tolerance to the regimen, and overall judgment of the condition. Patients with safety intolerance caused by any drug treatment will be reduced or discontinued according to the dosage adjustment plan specified in the regimen.

After completing the above treatments, the pathology, imaging, and cytology of the tumor site were obtained through diagnostic TURBT or cystoscopy for tumor evaluation to assess whether complete remission was achieved. The first tumor efficacy evaluation was conducted 3 months after receiving treatment, and the researcher judged whether to continue treatment based on the patient's treatment status. After completing the treatment for the next 3 months, another tumor efficacy evaluation was conducted. After completing all 12 treatment cycles (6 months), the patient underwent two tumor evaluations at the 6th month (from the 12th month of treatment) and the 12th month (from the 24th month of treatment), respectively.

MIBC has a poor prognosis, and even with radical surgery, the 5-year survival rate is less than 60%. Although immune checkpoint inhibitors have made rapid progress in the treatment of advanced bladder and urinary tract epithelial cancer in the past year, many drugs have been approved for market both domestically and internationally.

Immunosuppressants targeting PD-1 or its ligand PD-L1, including Nivolumab, Pembrolizumab, Trastuzumab, and Triprolizumab, have been proven to be a promising approach for tumor immunotherapy. The Phase III clinical trial of Pembrolizumab compared with chemotherapy for the treatment of advanced bladder and urinary tract epithelial cancer has been successful. Nivolumab has an objective efficacy rate of 24.4% in patients with advanced bladder and urinary tract epithelial cancer who have previously failed treatment. Domestic trastuzumab (targeting high PD-L1 expression) and terilelizumab have significantly improved ORR and OS in patients who have failed platinum based chemotherapy, and the DoR of beneficiary patients has been significantly prolonged. Therefore, the efficacy of anti-PD-1 monoclonal antibody in advanced bladder and urinary tract epithelial cancer has been validated. In PURE-01, Pembrolizumab achieved a complete disease response rate of 42% in preoperative neoadjuvant therapy for MIBC, greatly changing the treatment status. Terriptylimab also achieved a pCR rate of 40% in neoadjuvant therapy for MIBC.

Whether the bladder can be preserved in patients with localized MIBC has always been a hot topic in clinical research. The ANZUP 1502 study is a phase II clinical trial evaluating the combination of Pembrolizumab and concurrent chemoradiotherapy for the treatment of MIBC, with 90% of patients achieving complete remission after 24 weeks. At the same time, TMT combined with immunotherapy achieved good bladder preservation effects in both the IMMUNOPRESSE-SOGUG study (electrocautery durvalumab+Treme radiotherapy, 12 week cCR rate of 81%) and the BTCR-GU15-023 study (durvalumab+radiotherapy, cCR rate of 54.5%). Therefore, based on the excellent results of phase II clinical studies, there are currently multiple phase III clinical studies underway, including KEYNOTE-992, SWOG1806, SunRISe-2, INTACT studies, etc.

Vidiximab for injection (product code: RC48, RC48-ADC) is an innovative new therapeutic biologic developed to meet the needs of patients with HER2 expressing malignant solid tumors. The injection of vediximab mainly exerts anti-tumor effects through two pathways: one is to inhibit the activation of HER2 downstream signaling pathways (such as PI3K/AKT) by binding to HER2 molecules on the surface of tumor cells, thereby interfering with cell transcription, growth, and proliferation; The second is through the action of small molecule MMAE on microtubule proteins during mitosis, which interferes with the formation of microtubules in cells, mainly manifested as depolymerization of microtubules and induction of cell cycle arrest in the G2/M phase. RC48-C005/C09 is a combined analysis of two clinical studies, C005 and C009. The trial enrolled a total of 107 patients with advanced urothelial carcinoma who had previously received first-line or above systemic therapy but failed. Among all 107 patients, the ORR evaluated by IRC was 50.5% (95% CI: 40.6, 60.3), and the BOR evaluation results showed that 2 patients achieved CR and 52 patients achieved PR.

From a biological perspective, the combination of targeted therapy and immunotherapy can simultaneously block the HER2 signaling pathway and PD-1/PD-L1 signaling pathway, bridge PD-1 expressing T lymphocytes and HER2 expressing tumor cells, and assist T cells in recognizing and killing tumor cells. In addition, the warhead of ADC drugs can cause tumor cell destruction through cytotoxic effects (especially the destruction of microtubules by MMAE), and the release of calcitonin, heat shock proteins, and other substances on the surface of apoptotic cells can induce immunogenic cell death (ICD), thereby activating T cells. MMAE and other microtubule protein stabilizers (MSA) can directly activate antigen-presenting cells (such as dendritic cells), promote DC maturation, enhance T cell recruitment, and reduce immune suppression in tumor tissues. Therefore, the combination of anti-HER2ADC and PD-1/L1 drugs has a synergistic effect, which can improve the immunosuppressive effect in the tumor microenvironment and enhance the infiltration of immune cells into the tumor. In the RC48-C014 study, the combination of vediximab (RC48) and terilelimab (JS001) was used for mUC with previous first-line treatment failure or intolerance/unwillingness to receive cisplatin chemotherapy. The study results showed an objective response rate of 73.2%, with an objective response rate of 76% in the first-line population, including HER2 IHC (2+/3+) and PD-L1 (+); The objective response rates of HER2 IHC (2+/3+) and PD-L1 (-) patients were 75% and 87.5%, respectively. Meanwhile, there was no significant increase in treatment-related adverse reactions compared to monotherapy.

In the first phase of this study, 6 patients did not experience any DLT events within 28 days after receiving the study drug and radiotherapy. According to the definition of the first phase study, this protocol is considered safe. In the first stage of patients, the CR rate reached 83% in March, which has preliminarily returned to normal for its effectiveness. Therefore, based on the results of the first stage, further research will be conducted in the second stage.

Inclusion Criteria:

• Men or women aged ≥ 18 years old;

• ECOG PS:0～1;

• The subjects need to undergo maximum TURBT surgery (no need for secondary resection) and imaging diagnosis. The researchers have determined that MIBC (urothelial carcinoma as the main pathological component>50%) is present, and plan to undergo radical cystectomy, lymph node dissection, and urinary diversion surgery;

• cT2-T4a N0 M0 （CT/MRI ± PET/CT）;

• Accept maximum TURBT;

• Have tissue examination specimens with TURBT;

• Expected survival period ≥ 3 months;

• The immunohistochemical staining result of the tissue after the last TURBT surgery was IHC 2+or 3+;

• The main organ function is normal (14 days before enrollment), which meets the following criteria:

  1. The standard for blood routine examination must meet the following criteria: (no blood transfusion or treatment with granulocyte colony-stimulating factor within 14 days before enrollment):

     HB≥90 g/L； ANC≥1.5×109 /L； PLT≥100×109 /L；

  2. Non functional organic diseases must meet the following criteria:

T-BIL ≤ 1.5 × ULN (upper limit of normal value); ALT and AST ≤ 2.5 × ULN; If there is liver metastasis, ALT and AST should be ≤ 5 × ULN; Blood creatinine ≤ 1.5 × ULN or creatinine clearance rate (CrCl) calculated according to the Cockcroft Gault formula ≥ 50 mL/min; International normalized ratio (INR) and activated partial thromboplastin time (aPTT): ≤ 1.5 × ULN (this standard is only applicable to patients who have not received anticoagulant therapy); Patients receiving anticoagulant therapy should ensure that the anticoagulant is within the required treatment range;

• Have not received systemic corticosteroid treatment within 4 weeks prior to treatment;
• Men with reproductive ability or women with the possibility of pregnancy must use highly effective contraceptive methods during the trial (such as oral contraceptives, intrauterine devices, abstinence control or barrier contraception combined with spermicides), and continue contraception for 12 months after the end of treatment;
• The subjects voluntarily joined the study, signed informed consent forms, had good compliance, and cooperated with follow-up.

Exclusion Criteria:

• Previous treatment with anti-PD-1, anti-PD-L1, and anti-PD-L2, including adjuvant therapy phase;
• Individuals known to be allergic to recombinant humanized anti-PD-1 monoclonal antibody drugs and their components;
• Those who have received systemic chemotherapy, radiation therapy, or other anti-tumor treatments (including corticosteroid therapy, immunotherapy) or participated in other clinical studies within 4 weeks before the start of treatment, or have not yet recovered from the previous toxicity (excluding 2nd degree hair loss and 1st degree neurotoxicity);
• Pregnant or lactating women;
• Positive HIV test result;
• Active hepatitis B or C patients HBsAg or HBcAb positive individuals were simultaneously detected with HBV DNA copy number positivity (quantitative detection limit is 500IU/ml, or reaching the copy number positivity value detected by the research center); Patients of this type must undergo HBV DNA testing during screening studies; Patients with positive HCV antibody test results are only eligible for this study if their HCV RNA PCR test results are negative;
• Have a clear history of active tuberculosis;
• Active autoimmune diseases that require systematic treatment within the past 2 years (such as the use of disease regulating drugs, corticosteroids, or immunosuppressive drugs), allowing for related alternative treatments (such as thyroid hormone, insulin, or physiological corticosteroid replacement therapy for renal or pituitary dysfunction);
• Other serious and uncontrollable concomitant diseases that may affect the compliance of the scheme or interfere with the interpretation of the results, including active opportunistic infections or progressive (serious) infections, uncontrollable diabetes, cardiovascular diseases (Grade III or IV heart failure defined by the New York Heart Association classification, Grade II or above heart block, myocardial infarction, unstable arrhythmia or unstable angina pectoris in the past six months, cerebral infarction in three months, etc.) or lung diseases (interstitial pneumonia, obstructive pulmonary disease, and symptomatic bronchospasm history);
• Previously received live vaccination within 4 weeks before the start of treatment;
• Previously received allogeneic hematopoietic stem cell transplantation or solid organ transplantation;
• Significant surgical procedures (excluding diagnostic surgeries or TURBT) performed within the 4 weeks prior to the start of treatment;
• Individuals with a history of substance abuse and inability to quit, or those with a history of mental disorders;
• Large amounts of pleural or ascites accompanied by clinical symptoms or requiring symptomatic treatment;
• In the past 5 years, have had other malignant tumors that have not been cured, but do not include malignant tumors that have been clearly cured, or curable cancers such as basal or squamous cell carcinoma, localized low-risk prostate cancer, cervical in situ cancer, or breast in situ cancer; Note: Localized low-risk prostate cancer (defined as patients with stage ≤ T2b, Gleason score ≤ 7, and PSA ≤ 20ng/mL (as measured) at the time of prostate cancer diagnosis who have received curative treatment and have no biochemical recurrence of prostate-specific antigen (PSA) may participate in this study);
• Simultaneous presence of upper urinary tract urothelial carcinoma (renal pelvis, ureteral urothelial carcinoma);
• According to the researcher's perspective, there may be increased risks associated with participating in the study, or other severe, acute, or chronic medical or mental illnesses or laboratory abnormalities that may interfere with the interpretation of the research results.