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.
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.
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.