TACE Combined With Thermal Ablation and ADC, PD-1, and Chemotherapy as First-line Treatment for HER2-highly-expressing Gastric Cancer With Liver Metastases: A Multicenter, Single-arm Prospective Clinical Study.

TACE Combined With Thermal Ablation and Antibody-drug Conjugates, Immune Checkpoint Inhibitors, and Chemotherapy as First-line Treatment for HER2-highly-expressing Gastric Cancer With Liver Metastases: a Multicenter, Single-arm Prospective Clinical Study.

This study is a multicenter, single-arm prospective clinical trial designed to evaluate the efficacy of TACE combined with thermal ablation, antibody-drug conjugates, immune checkpoint inhibitors, and first-line chemotherapy for the treatment of HER2 - highly expressing gastric cancer with liver metastases.

Inclusion Criteria:

1. Participants voluntarily joined this study, signed informed consent forms, demonstrated good compliance, and cooperated with follow-up.
2. Male or female, aged 18 or older and 75 or younger;
3. ECOG score is 0-1;
4. Expected survival time ≥ 3 months;
5. Imaging examinations suggest gastric cancer with liver metastasis;
6. Histopathologically confirmed gastric adenocarcinoma and liver metastatic adenocarcinoma;
7. Enhanced CT scans were used to observe the staining of liver metastases; tumors with good blood supply were included in this study.
8. Immunohistochemical results of gastric adenocarcinoma and/or liver metastatic adenocarcinoma confirmed high expression of HER2 (defined as: IHC 2+ or 3+);
9. No prior history of antibody-drug conjugate ( ADC ) therapy ; Note: Patients who have relapsed more than 6 months after receiving neoadjuvant (radiotherapy) chemotherapy + radical surgery, or who have relapsed more than 6 months after completing adjuvant (radiotherapy) chemotherapy or radical concurrent chemoradiotherapy;
10. Within 28 days prior to the first administration of the study drug, the target lesion had not received local treatment (including transarterial chemoembolization/TACE, hepatic artery infusion chemotherapy/TAC, radiotherapy, radiation embolization or ablation, etc.);
11. There must be at least one liver metastasis meeting the following criteria:

At least one patient is eligible for TACE and/or thermal ablation treatment; 12. In addition to the ablated lesion, there is at least one measurable lesion in the liver or outside the liver (according to RECIST 1.1 criteria, the long axis of the tumor lesion on CT scan is ≥10 mm, and the short axis of the lymph node lesion on CT scan is ≥10 mm) (for assessing the remote effect).

1.3 . Damage caused by other treatments received by the subject has recovered, including those received other cytotoxic drugs, radiotherapy or surgery for ≥4 weeks, and the wounds have completely healed ; 1.4 . Subjects should not have previously received anti-PD-1, PD-L1, CTLA-4, or CAR-T immunotherapy ; 1.5 . Asymptomatic brain metastases or control of brain metastases after radiotherapy ; 1.6 . Major organ functions are normal, and subjects must meet the following laboratory indicators:

1)In the absence of granulocyte colony-stimulating factor use in the past 14 days, the absolute neutrophil count (ANC) is ≥1.5 x 10⁹ /L .

2)10⁹ /L without blood transfusion in the past 14 days ; 3)Hemoglobin >9 g/dL in the absence of blood transfusion or erythropoietin use within the past 14 days ; 4)There is no active bleeding, such as hematemesis, melena, gingival bleeding, epistaxis, or hemorrhoidal bleeding, and the fecal occult blood test is ≤ +.

5)Total bilirubin ≤1.5 × upper limit of normal (ULN); 6)Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5.0×ULN , alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN, and total serum bilirubin (TBIL) ≤1.5×ULN.

7)Serum creatinine ≤1.5×ULN or creatinine clearance ( CrCl ) ≥50 mL/min calculated according to the Cockcroft-Gault formula; For women: CrCl = (140 - age × weight (kg) × 0.85 / 72 × serum creatinine (mg/dL)) For males: CrCl = (140 - age × weight (kg) × 1.00 / 72 × serum creatinine (mg/dL)) 8)Good coagulation function is defined as an international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 times the ULN; and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; (For patients receiving anticoagulation therapy, such as those taking anticoagulants like aspirin , warfarin, or clopidogrel , the medication should generally be discontinued for at least 5-7 days, and the investigator should determine that both INR and APTT are within a safe and effective therapeutic range).

9)Normal thyroid function is defined as thyroid-stimulating hormone (TSH) within the normal range. If baseline TSH exceeds the normal range, subjects with normal total T3 (or FT3) and FT4 may also be enrolled.

10)Cardiac enzyme levels within the normal range (simply laboratory abnormalities that are not clinically significant, as determined by the researchers, are also allowed to be enrolled); 11)Doppler ultrasound assessment showed a left ventricular ejection fraction (LVEF) ≥ 50%.

1.7 . Patients with potential fertility need to use a medically approved contraceptive method (such as an intrauterine device, birth control pill, or condom) during the study treatment period and for one month after the end of the study treatment period; and must have a negative serum or urine HCG test within 72 hours before study enrollment, and must not be breastfeeding.

Exclusion Criteria:

Subjects meeting the following criteria were not eligible for inclusion in this study:

1. diagnosed with other malignant tumors within 5 years prior to the first dose and who are not cured (excluding radically resected basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or carcinoma in situ that has been radically removed);
2. Currently participating in interventional clinical research treatment, or having received other investigational drugs or used investigational devices within 4 weeks prior to the first dose;
3. Previous treatment with the following: antibody-drug conjugates, anti-PD-1, anti-PD-L1 or anti-PD-L2 drugs or drugs that stimulate or co-inhibit T cell receptors (e.g. CTLA-4, OX-40, CD137);
4. Within 28 days prior to the first administration of the study drug, the target lesion had received local treatment (including transarterial chemoembolization/TACE, hepatic artery infusion chemotherapy/TAC, radiotherapy, radioembolization or ablation, etc.);
5. The patient had received systemic treatment with traditional Chinese medicine or immunomodulatory drugs with antitumor indications within 2 weeks prior to the first dose ;
6. Subjects with any active autoimmune disease or a history of autoimmune disease (such as, but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, pituitary inflammation, vasculitis, nephritis, hyperthyroidism, hypothyroidism; subjects with vitiligo or whose childhood asthma was completely remitted and requires no intervention in adulthood are eligible to be included; subjects with asthma requiring medical intervention with bronchodilators are not eligible to be included).
7. Subjects are currently using immunosuppressants, or systemic or absorbable topical corticosteroids, to achieve immunosuppression (dose >10 mg/ day prednisone or other equivalent corticosteroids), and have continued to use them within 2 weeks prior to enrollment; Note: Physiological doses of glucocorticoids (≤10 mg/day prednisone or equivalent drugs) are permitted.
8. Known allogeneic organ transplantation (excluding corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
9. known hypersensitivity to the study drugs vedicetumab , sintilimab, and tegafur ;
10. Active gastrointestinal bleeding or high risk of bleeding within 2 weeks prior to screening; or gastrointestinal perforation/fistula within 6 months prior to screening; intestinal obstruction, within 30 days after major surgery, uncontrolled hypertension, NYHA class III-IV heart failure, or severe hepatic or renal failure (class 4).
11. Prior to starting treatment, the individual has not fully recovered from any toxicity and/or complications caused by any intervention (i.e., ≤ grade 1 or at baseline, excluding fatigue or hair loss).
12. Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1/2 antibody positive );
13. Untreated active hepatitis B (defined as HBsAg positive and HBV-DNA copy number greater than the upper limit of normal value in the laboratory of the research center);

Note : Hepatitis B subjects who meet the following criteria may also be enrolled :

1. before the first dose , the subject should receive anti-HBV therapy throughout the study chemotherapy treatment to avoid viral reactivation.
2. Subjects with positive, negative, anti-HBs, or negative HBV viral loads do not require prophylactic anti-HBV treatment, but close monitoring for viral reactivation is necessary.

14.Subjects with active HCV infection (HCV antibody positive and HCV-RNA level above the detection limit); 15.Those who have received a live vaccine within 4 weeks prior to screening or plan to receive any vaccine during the study period (Note: Injectable inactivated virus vaccines against seasonal influenza are permitted within 30 days prior to the first dose; however, intranasal live attenuated influenza vaccines are not permitted).

16.Pregnant or breastfeeding women; 17.The presence of any serious or uncontrollable systemic disease, such as:

1. Significant and uncontrollable abnormalities in rhythm, conduction, or morphology on resting electrocardiogram, such as complete left bundle branch block, second-degree or higher cardiac conduction block, ventricular arrhythmia, or atrial fibrillation.
2. According to NYHA standards, heart failure is classified as grade III or IV, or echocardiography shows a left ventricular ejection fraction (LVEF) <50%; unstable angina, congestive heart failure, or NYHA grade 3 or higher heart failure.
3. Subjects who had experienced acute cardiovascular and cerebrovascular diseases such as acute cerebral infarction or acute coronary syndrome within one month, and whose cardiovascular clinical symptoms or diseases were not well controlled;
4. A history of non-infectious pneumonia requiring glucocorticoid therapy within one year prior to the first dose, or current clinically active interstitial lung disease;
5. Active pulmonary tuberculosis;
6. prior to the first use of the study drug , such as severe pneumonia, bacteremia, or infectious complications requiring hospitalization; baseline chest imaging showed active lung inflammation; symptoms and signs of infection existed within 2 weeks prior to the first use of the study drug; or oral and intravenous antibiotics were required, excluding prophylactic antibiotic use.
7. The patient presents with clinically active diverticulitis, abdominal abscess, and gastrointestinal obstruction.
8. Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
9. Patients with a clear tendency to gastrointestinal bleeding include those with the following conditions: active local ulcer lesions and fecal occult blood (++) {those with ++ are not eligible}; those with a history of melena or hematemesis within the past 2 months;
10. Those with abnormal coagulation function (INR>1.5 APTT>1.5 ULN) and bleeding tendency;
11. Long-term unhealed wounds or fractures; major surgery or severe traumatic injury, fracture or ulcer within 4 weeks;
12. Poorly controlled diabetes (fasting blood glucose (FBG) > 10 mmol/L);
13. Urinalysis results indicate urine protein ≥++, and 24-hour urine protein quantification is confirmed to be >1.0 g;
14. Patients with mental disorders who are unable to cooperate with treatment;
15. Patients requiring treatment and with a history of lung disease that could potentially affect surgery include, but are not limited to, interstitial lung disease, non-infectious pneumonia, pulmonary fibrosis, and acute lung disease.
16. The patient presents with clinically active diverticulitis, abdominal abscess, and gastrointestinal obstruction.
17. Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
18. Patients with mental disorders who are unable to cooperate with treatment;
19. The presence of systemic diseases that researchers have determined are not stably controlled, including diabetes and hypertension; 18.Candidates must have a history of active autoimmune disease requiring systemic treatment (such as immunomodulatory drugs, corticosteroids, or immunosuppressants) within the past two years prior to screening, with permitted replacement therapy (such as thyroxine, insulin, or physiological corticosteroid replacement therapy for renal or pituitary insufficiency), or a history of refractory autoimmune disease. Candidates must have used systemic steroids (dose > 10 mg/day prednisone or equivalent dose of other glucocorticoids) or other systemic immunosuppressive therapies within 14 days prior to screening.

19.Patients must have had other malignant tumors within the 5 years prior to screening, except for those that have been cured by treatment (including but not limited to adequately treated thyroid cancer, cervical carcinoma in situ, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated with radical surgery).

20.Known allogeneic organ transplantation (excluding corneal transplantation) or allogeneic hematopoietic stem cell transplantation; 21.Prior to starting treatment, the individual has not fully recovered from any toxicity and/or complications caused by any intervention (i.e., ≤ grade 1 or at baseline, excluding fatigue or hair loss).

22.Medical history or disease evidence that may interfere with trial results, prevent participants from participating in the study throughout the process, abnormal treatment or laboratory test values, or other circumstances that the investigator deems unsuitable for enrollment.