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

Prospective, Single-Arm, Single-Center Phase II Clinical Study of Iparomlimab Tolvorlimab as Neoadjuvant Immunotherapy for Locally Advanced Gastric Adenocarcinoma With Microsatellite Instability/Mismatch Repair Deficiency

Study Background

1. Clinical Rationale and Unmet Medical Need Gastric cancer is the 5th most common malignancy and the 3rd leading cause of cancer death worldwide. China accounts for >40% of global new cases, with nearly 90% of patients diagnosed at locally advanced stages and a 5-year overall survival (OS) rate of only 10%-49%. East Asia alone represents 58% of the global gastric cancer burden, with China reporting approximately 400,000 new cases and high mortality annually.

   Although D2 radical gastrectomy remains the standard surgical treatment, local recurrence rates after surgery alone range from 24% to 54%, with most recurrences occurring within 2 years. Neoadjuvant chemotherapy is recommended by NCCN, ESMO, JGCA, and CSCO guidelines for locally advanced gastric cancer. However, the microsatellite instability-high/mismatch repair-deficient (dMMR/MSI-H) subtype demonstrates poor response to chemotherapy but exceptional sensitivity to immunotherapy. Currently, no consensus exists on the optimal perioperative treatment for this population, and CSCO guidelines only recommend clinical trial participation or active surveillance.

2. Immunotherapy Advances in dMMR/MSI-H Gastric Cancer Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have revolutionized the treatment of dMMR/MSI-H tumors by restoring anti-tumor immune responses. The phase II KEYNOTE-585 study (NCT03221426), the largest trial of neoadjuvant PD-1 monotherapy in this population, demonstrated a pathological complete response (pCR) rate of 32.8%, objective response rate (ORR) of 65.3%, and 3-year progression-free survival (PFS) rate of 78.5%-significantly superior to traditional chemotherapy (pCR 12.3%, 3-year PFS 52.1%). A phase II study of sintilimab monotherapy reported a pCR rate of 34.2%, major pathological response (MPR) rate of 52.2%, and grade ≥3 treatment-related adverse event (TRAE) rate of only 8.7%.

   Dual immune checkpoint blockade further improves efficacy. The INFNITY study showed that neoadjuvant tremelimumab plus durvalumab achieved a pCR rate of 60% and MPR rate of 80% in 18 patients with resectable dMMR/MSI-H gastric adenocarcinoma. These data confirm that immunotherapy, particularly dual checkpoint inhibition, offers superior efficacy and acceptable safety compared to chemotherapy in this patient subset.

3. Study Agent: Apalimab/Tovorilimab (QL1706) Apalimab/Tovorilimab (QL1706) is a first-in-class bifunctional combination antibody developed using the MabPair® technology platform. It comprises anti-PD-1 antibody (apalimab) and anti-CTLA-4 antibody (tovorilimab) in a 2:1 molar ratio, simultaneously blocking both immune checkpoint pathways for synergistic anti-tumor activity.

   Compared to separate administration of PD-1 and CTLA-4 inhibitors, QL1706 offers improved pharmacokinetics, enhanced targeting specificity, reduced off-target effects, lower TRAE rates, and simplified dosing (single infusion) that improves patient adherence. Clinical trials have demonstrated promising efficacy and safety across multiple tumor types:

   Cervical cancer (DUBHE-C-206): ORR 33.8%, disease control rate (DCR) 64.9%, median PFS 5.4 months in platinum-refractory recurrent/metastatic disease Hepatocellular carcinoma (DUBHE-H-308): ORR 40%, median PFS 8.1 months, 12-month OS rate 73.3% in combination with bevacizumab Non-small cell lung cancer (DUBHE-L-201): Median PFS 8.51 months, median OS 26.51 months, grade ≥3 TRAE rate 35.5% in combination with chemotherapy and bevacizumab

4. Study Objectives and Significance This is a prospective, single-arm, single-center phase II clinical trial designed to evaluate the efficacy and safety of QL1706 as neoadjuvant therapy in patients with dMMR/MSI-H locally advanced gastric adenocarcinoma. The primary objective is to assess the pCR rate, with secondary objectives including ORR, MPR rate, R0 resection rate, PFS, OS, and safety profile.

This study will provide critical clinical evidence for the use of QL1706 in the neoadjuvant setting. The results will: (1) establish a new treatment option for dMMR/MSI-H gastric cancer patients; (2) lay the foundation for subsequent multicenter randomized phase III trials; (3) explore potential predictive biomarkers of response and resistance mechanisms; and (4) investigate the feasibility of surgery-sparing strategies for selected patients with exceptional response. Ultimately, this trial has the potential to transform the perioperative treatment paradigm for dMMR/MSI-H gastric cancer and improve patient outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: Iparomlimab/Tuvonralimab (QL1706)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhaode Bu, Ph.D; Phone Number: 0086-10-88196970; Email: dr.guohaiyang@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The subject voluntarily enrolls in this study, is able to provide signed informed consent, and has good compliance.
2. Aged 18 to 75 years (at the time of signing informed consent), male or female.
3. 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.
4. Tumor biopsy demonstrates dMMR status and concurrently meets the criteria for MSI-H.
5. ECOG performance status score of 0 to 1.
6. Expected survival ≥ 6 months.
7. 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%.
8. 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:

1. 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).
2. 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.
3. 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.
4. 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.
5. 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.
6. History of allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.
7. Known hypersensitivity to any study drug used in this study.
8. Peripheral neuropathy ≥ Grade 2.
9. Known history of human immunodeficiency virus (HIV) infection (i.e., positive HIV 1/2 antibody).
10. 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.
11. Pregnant or lactating female subjects.
12. 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.
13. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Iparomlimab/Tuvonralimab (QL1706) Neoadjuvant and Adjuvant Immunotherapy; All eligible patients will receive a fixed perioperative treatment regimen consisting of neoadjuvant immunotherapy, radical surgery, and adjuvant immunotherapy: Neoadjuvant Phase: Iparomlimab/tovorilimab (QL1706) 5 mg/kg administered as an intravenous infusion on Day 1 of each 3-week cycle, for a total of 4 cycles. Surgical Phase: Radical D2 gastrectomy will be performed 4-8 weeks after the last dose of neoadjuvant therapy, according to standard surgical practice for gastric cancer. Adjuvant Phase: Patients who recover adequately from surgery will receive an additional 4 cycles of iparomlimab/tovorilimab (QL1706) 5 mg/kg intravenously every 3 weeks, starting 4-6 weeks postoperatively. Dosing may be delayed or adjusted based on treatment-related adverse events graded according to the NCI-CTCAE version 5.0 criteria. Patients will be monitored for safety throughout the treatment period and followed for long-term survival outcomes.

Drug: Iparomlimab/Tuvonralimab (QL1706); In this study, QL1706 is administered as a single-agent immunotherapy in the perioperative setting for patients with locally advanced dMMR/MSI-H gastric or gastroesophageal junction adenocarcinoma. The intervention consists of: Neoadjuvant phase: 5 mg/kg intravenous infusion on Day 1 of each 3-week cycle, for a total of 4 cycles Adjuvant phase: 5 mg/kg intravenous infusion on Day 1 of each 3-week cycle, for an additional 4 cycles, starting 4-6 weeks after radical D2 gastrectomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response (pCR) Rate	The proportion of subjects with no residual viable tumor cells identified under microscopic examination of the surgically resected specimen, and no evidence of lymph node metastasis (ypT0N0).	Assessed at the time of radical gastrectomy, which is performed 4-8 weeks after completion of neoadjuvant therapy.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response (MPR) Rate	Proportion of subjects with ≤10% residual viable tumor cells in the surgically resected specimen.	Assessed at the time of radical gastrectomy (4-8 weeks after completion of neoadjuvant therapy)
Objective Response Rate (ORR)	Proportion of subjects who achieve a complete response (CR) or partial response (PR) based on radiological assessment.	Assessed within 1 week before radical gastrectomy (4-8 weeks after completion of neoadjuvant therapy)
3-Year Event-Free Survival (EFS) Rate	Proportion of subjects who are alive and free of any of the following events at 3 years: disease progression precluding surgery, local or distant recurrence, or death from any cause.	From study enrollment to 3 years post-enrollment, assessed every 6 months
3-Year Disease-Free Survival (DFS) Rate	Proportion of subjects who underwent radical surgery and are alive and free of disease recurrence or death from any cause at 3 years.	From radical gastrectomy to 3 years post-surgery, assessed every 6 months
Overall Survival (OS)	Time from pathological diagnosis of gastric adenocarcinoma to death from any cause.	From study enrollment to study completion (3 years), assessed every 6 months
Incidence of Treatment-Related Adverse Events (TRAE)	Incidence, severity, and type of adverse events related to neoadjuvant and adjuvant study drug administration.	From first study drug administration to 30 days after the last study drug administration

Collaborators and Investigators

• Sponsor: Peking University Cancer Hospital & Institute

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: May 12, 2026
• First Submitted That Met QC Criteria: May 12, 2026
• First Posted (Actual): May 19, 2026

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms
• Other Study ID Numbers: LGH2026123

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared due to ethical concerns, privacy regulations, institutional policies, and the small sample size of this single-center phase II study. Aggregate study results will be published in scientific journals.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No