Iparomlimab Tolvorlimab as Neoadjuvant Immunotherapy for Locally Advanced Gastric Adenocarcinoma With Microsatellite Instability/Mismatch Repair Deficiency

Gastric cancer is the fifth most common malignancy and third leading cause of cancer death worldwide. China bears over 40% of global new cases, with nearly 90% presenting at locally advanced stages and 5-year survival of only 10%-49%. Neoadjuvant chemotherapy is standard for locally advanced gastric cancer, but the dMMR/MSI-H subtype is chemotherapy-resistant and highly sensitive to immunotherapy. PD-1 inhibitors have shown promising pCR rates of 32%-34% in this population, and dual checkpoint blockade further improves efficacy.

Iparomlimab/tuvonralimab (QL1706) is a first-in-class bispecific PD-1/CTLA-4 combination antibody with synergistic activity, favorable pharmacokinetics, and manageable safety. This single-arm phase II trial evaluates QL1706 as neoadjuvant and adjuvant therapy in resectable locally advanced dMMR/MSI-H gastric or gastroesophageal junction adenocarcinoma (AJCC 8th stage II-III).

Eligible patients (18-75 years, ECOG 0-1, treatment-naïve, adequate organ function) receive 4 cycles of neoadjuvant QL1706 5 mg/kg q3w, followed by radical surgery 4-8 weeks later, then 4 cycles of adjuvant QL1706. The primary endpoint is pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR), objective response rate (ORR), 3-year event-free survival (EFS), 3-year disease-free survival (DFS), overall survival (OS), safety, and exploratory biomarkers. Adverse events are graded per NCI-CTCAE 5.0; surgical complications per Clavien-Dindo.

Based on historical pCR of 28% with PD-1 monotherapy, QL1706 is expected to achieve 50% pCR. With one-sided α=0.05 and power=90%, 24 patients are required; 30 patients will be enrolled to account for 15% dropout.

This study will evaluate the efficacy and safety of QL1706 in the perioperative setting, establish a new therapeutic option for dMMR/MSI-H gastric cancer, and support future phase III development.

Inclusion criteria

• The subject voluntarily enrolls in this study, is able to provide signed informed consent, and has good compliance.
• Aged 18 to 75 years (at the time of signing informed consent), male or female.
• Histologically confirmed gastric adenocarcinoma, clinically staged as Stage II-III (locally advanced) per AJCC 8th edition based on endoscopic ultrasound or contrast-enhanced CT/MRI scan. The subject agrees to undergo radical resection, and the lesion is assessed as resectable by the investigator. No prior systemic therapy for the current disease, including anti-tumor chemotherapy, radiotherapy, or immunotherapy.
• Tumor biopsy demonstrates dMMR status and concurrently meets the criteria for MSI-H.
• ECOG performance status score of 0 to 1.
• Expected survival ≥ 6 months.
• Adequate major organ function, meeting the following criteria: a) Routine blood test (without blood transfusion or hematopoietic stimulating agents within 14 days): Hemoglobin (Hb) ≥ 90 g/L; Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L; Platelets (PLT) ≥ 100 × 10⁹/L; b) Blood biochemistry: Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5 × ULN; Total Bilirubin (TBIL) ≤ 1.5 × ULN; Serum Creatinine (Cr) ≤ 1.5 × ULN, or creatinine clearance ≥ 60 mL/min; Coagulation function: Activated Partial Thromboplastin Time (APTT), International Normalized Ratio (INR), Prothrombin Time (PT) ≤ 1.5 × ULN; c) Doppler echocardiography: Left Ventricular Ejection Fraction (LVEF) ≥ 50%.
• Subjects of reproductive potential must use an effective contraceptive method during the study and for 120 days after study completion. Female subjects must have a negative serum pregnancy test within 7 days prior to enrollment and must not be breastfeeding.

Exclusion criteria

• History of other malignant diseases other than gastric cancer diagnosed within 5 years prior to the first dose (excluding radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, radically resected carcinoma in situ, and papillary thyroid carcinoma curable by local treatment).
• Currently participating in an interventional clinical study, or having received other investigational medicinal products or investigational device therapy within 4 weeks prior to the first dose.
• Received systemic therapy with Chinese patent medicine with anti-tumor indications or immunomodulatory agents (including thymosin, interferon, interleukin, excluding local use for pleural effusion control) within 2 weeks prior to the first dose.
• History of active autoimmune disease requiring systemic therapy (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) is not considered systemic therapy.
• Receiving systemic corticosteroid therapy (excluding nasal, inhaled, or other topical corticosteroids) or any other form of immunosuppressive therapy within 7 days prior to the first dose.Note: Physiological doses of corticosteroids (≤10 mg/day prednisone or equivalent) are permitted.
• History of allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.
• Known hypersensitivity to any study drug used in this study.
• Peripheral neuropathy ≥ Grade 2.
• Known history of human immunodeficiency virus (HIV) infection (i.e., positive HIV 1/2 antibody).
• Received live vaccine within 30 days prior to the first dose (Day 1 of Cycle 1). Note: Inactivated seasonal influenza vaccine by injection within 30 days prior to the first dose is permitted; however, live attenuated influenza vaccine administered intranasally is not permitted.
• Pregnant or lactating female subjects.
• Presence of any severe or uncontrolled systemic disease, such as: a) Significant and symptomatic uncontrolled abnormalities in cardiac rhythm, conduction, or morphology on resting ECG; b) Unstable angina pectoris, congestive heart failure, chronic heart failure with NYHA class ≥ 2; c) Any arterial thrombosis, embolism, or ischemia within 6 months prior to enrollment, such as myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack; d) History of non-infectious pneumonitis requiring corticosteroid therapy within 1 year prior to the first dose, or current clinically active interstitial lung disease; e) Active pulmonary tuberculosis; f) Active or uncontrolled infection requiring systemic therapy; g) Clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction; h) Liver disease such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis; i) Urinalysis showing urine protein ≥ ++ and confirmed 24-hour urine protein > 1.0 g; j) Mental disorders that prevent cooperation with study treatment.
• Presence of medical history, abnormal findings, or laboratory abnormalities that may interfere with study results or prevent the subject from completing the study; or any other conditions deemed by the investigator to be inappropriate for enrollment or to pose other potential risks.