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.
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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
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
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).
Time frame: Assessed at the time of radical gastrectomy, which is performed 4-8 weeks after completion of neoadjuvant therapy.
Major Pathological Response (MPR) Rate
Proportion of subjects with ≤10% residual viable tumor cells in the surgically resected specimen.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: From first study drug administration to 30 days after the last study drug administration
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