Conversion therapy using disitamab vedotin (RC48), sintilimab, and SOX for HER2 IHC 1+ or 2+ unresectable gastric cancer

Efficacy and Safety of RC48 (Disitamab Vedotin) Combined With Sintilimab and SOX for HER2 IHC 1+/2+ Unresectable Locally Advanced or Advanced Gastric Cancer Conversion Therapy

This trial will test whether combining disitamab vedotin (RC48), the immunotherapy sintilimab, and SOX chemotherapy can shrink tumors enough to allow surgery in people with initially unresectable HER2 IHC 1+ or 2+ gastric cancer.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: Fudan University (Academic / other)
• Drugs / interventions: disitamab, prednisone, sintilimab
• Locations: 1 site (Shanghai, Shanghai Municipality)
• Trial ID: NCT07194005 on ClinicalTrials.gov

What this trial studies

This open-label, single-arm phase 2 trial gives disitamab vedotin plus sintilimab and SOX chemotherapy to patients with HER2 IHC 1+ or 2+ locally advanced or metastatic gastric adenocarcinoma who have a single initial unresectable factor. Participants receive 4 to 6 treatment cycles with tumor imaging every 6 to 12 weeks to monitor response. Patients who meet criteria for operability will undergo surgical resection and receive investigator-directed postoperative therapy, while those who do not may continue the regimen or switch treatment per investigator decision. The primary endpoint is the R0 resection rate to measure successful conversion to resectability.

Who should consider this trial

Good fit: Adults 18–70 with histologically confirmed unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2 IHC 1+ or 2+, a single initial unresectable factor, measurable disease, ECOG 0–1, adequate organ function, and no prior systemic anticancer therapy are the intended candidates.

Not a fit: Patients with HER2 0 or 3+ tumors, multiple unresectable factors, poor performance status, prior systemic therapy, or inadequate organ function are unlikely to be eligible or to benefit from this regimen.

Why it matters

Potential benefit: If successful, the regimen could convert unresectable tumors to operable disease and enable potentially curative surgery.

How similar studies have performed: Antibody–drug conjugates like disitamab vedotin have shown activity in HER2-low gastric cancer and early trials combining ADCs with PD‑1 inhibitors and chemotherapy have produced responses, but using this specific combination as conversion therapy is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Voluntarily enrolled and provided written informed consent;
2. Aged 18-70 years (inclusive), male or female;
3. Histologically and/or cytologically confirmed unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma;
4. No prior systemic anticancer therapy;
5. HER2 immunohistochemistry (IHC) result of 2+ or 1+, based on either previous test results (confirmed by the investigator) or central laboratory assessment;
6. Presence of a single initial unresectable factor;
7. At least one measurable lesion per RECIST 1.1;
8. Life expectancy ≥ 6 months;
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1;
10. Adequate organ function, defined as follows:

Hematological (within 14 days prior to screening, without transfusion or granulocyte colony-stimulating factor \[G-CSF\] support):

1. Hemoglobin ≥ 90 g/L;
2. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L;
3. White blood cell count ≥ 3.0 × 10⁹/L;
4. Platelet count ≥ 80 × 10⁹/L;

   Biochemical (within 14 days prior to screening, without albumin infusion):
5. Albumin ≥ 28 g/L;
6. Total bilirubin ≤ 2 × upper limit of normal (ULN);
7. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 × ULN in the absence of liver metastases; or ≤ 5 × ULN if liver metastases are present;
8. Serum creatinine ≤ 1.5 × ULN; or creatinine clearance (CrCl) ≥ 50 mL/min as calculated by the Cockcroft-Gault formula;

   Coagulation:
9. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN;
10. Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

Exclusion Criteria:

1. History of malignancies other than gastric cancer, with the following exceptions:

   1. Malignancies treated with curative intent and with no evidence of disease for 5 years;
   2. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder cancer, cervical carcinoma in situ, or other in situ carcinomas.
2. Conditions affecting the absorption, distribution, metabolism, or excretion of the investigational drug(s) (e.g., severe vomiting, chronic diarrhea, intestinal obstruction, malabsorption, etc.).
3. Previous allogeneic stem cell or solid organ transplantation.
4. Prior systemic antitumor therapy (including Chinese herbal medicine with antitumor indications) completed less than 4 weeks before the first dose of study treatment, or with prior treatment-related adverse events not recovered to ≤ CTCAE grade 1 (except for alopecia or pigmentation).
5. History or presence of congenital or acquired immunodeficiency disorders.
6. Active or previously documented autoimmune or inflammatory disorders (including but not limited to autoimmune hepatitis, interstitial pneumonia, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, uveitis, hypophysitis, hyperthyroidism, hypothyroidism, asthma requiring bronchodilators, etc.). Patients with vitiligo, childhood asthma that has fully resolved without intervention in adulthood, or other conditions deemed eligible by the investigator may be included.
7. Use of systemic immunosuppressive therapy within 2 weeks prior to enrollment, or anticipated need for such therapy during the study, with the following exceptions:

   1. Intranasal, inhaled, topical, or local corticosteroid injections (e.g., intra-articular);
   2. Systemic corticosteroids at a dose ≤ 10 mg/day prednisone or equivalent;
   3. Prophylactic corticosteroids for hypersensitivity reactions.
8. Known or suspected history of hypersensitivity to disitamab vedotin, anti-PD-1 agents, chimeric or humanized antibodies or fusion proteins, or any excipient of the investigational drug(s).
9. History of thrombotic or thromboembolic events within the past 6 months, such as stroke and/or transient ischemic attack, deep vein thrombosis, pulmonary embolism, etc.
10. Patients assessed by the physician to be at significant risk of bleeding, including but not limited to:

    * Major bleeding (\>30 mL within 3 months) or hemoptysis (\>5 mL within 4 weeks); endoscopic evaluation may be performed to confirm eligibility;
    * Active bleeding or coagulation disorders;
    * Bleeding tendency or current use of thrombolytic, anticoagulant, or antiplatelet therapy.

Where this trial is running

Shanghai, Shanghai Municipality

• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (Recruiting)

Study contacts

• Study coordinator: Xiaowen Liu

Conditions Gastric Cancer; gastric cancer; disitamab vedotin; conversion therapy