Factors Influencing Immunotherapy Response in dMMR/MSI-H Gastric/Gastroesophageal Junction Adenocarcinoma

NCT07259473 | Not Yet Recruiting Phase 2

• 1 other identifier: B2025-541R
• Study Type: interventional
• Target: 15
• Locations: 0 countries
• Sites: N/A

Brief Summary

dMMR/MSI-H is a key molecular subtype of gastric cancer, found in 8-22% of cases. It is typically associated with older age, female sex, distal tumor location, and intestinal histology (Lauren classification). While this subtype predicts better survival in locally advanced disease, its prognostic role in metastatic settings is less clear. Notably, dMMR/MSI-H tumors are often resistant to conventional chemotherapy. Conversely, they demonstrate exceptional sensitivity to immunotherapy. This has led to effective strategies using immune checkpoint inhibitors, either alone or combined with chemotherapy, in both neoadjuvant and advanced disease settings. However, key challenges remain. Prospective data are largely from Western populations, leaving the efficacy in Asian patients-who bear a high disease burden-less defined. Furthermore, about half of dMMR/MSI-H patients exhibit primary or acquired resistance to immunotherapy. A deeper understanding of the tumor-immune dynamics during treatment is crucial to uncover resistance mechanisms and improve patient outcomes.

Conditions

Gastric / Gastroesophageal Junction Adenocarcinoma; Mismatch Repair Deficient or MSI-High Solid Tumors; Immunotherapy

Outcome Measures

Primary Outcomes (1)

• Rate of pathological complete response

  The proportion of subjects exhibiting no residual tumor cells in the surgical specimen and the absence of positive lymph nodes (i.e., a pathological stage of ypT0N0).

  From the initiation of treatment to the date of surgery, an average of 14 weeks.

Secondary Outcomes (5)

• Major Pathological Response Rate

  From the initiation of treatment to the date of surgery, an average of 14 weeks.

• ypN stage

  From the initiation of treatment to the date of surgery, an average of 14 weeks.

• R0 resection rate

  From the initiation of treatment to the date of surgery, an average of 14 weeks.

• Event-free Survival

  The time from the initiation of treatment until disease progression, disease recurrence, death from any cause, or 3 years since enrollment.

• Overall Survival

  From the initiation of treatment until death from any cause or 3 years since enrollment.

Study Arms (1)

dMMR/MSI-H GC

EXPERIMENTAL

Immunotherapy with induction chemotherapy

Drug: Immunotherapy; Drug: Induction chemotherapy; Procedure: D2 radical gastrectomy

Interventions

Immunotherapy DRUG

Drug: Immune checkpoint inhibitors (ICIs), specifically PD-1 antibodies, PD-L1 antibodies, PD-1/CTLA-4 bispecific antibodies, or PD-1/CTLA-4 combination therapy. Regimen: 4 treatment cycles.

dMMR/MSI-H GC

Induction chemotherapy DRUG

Drug: Oxaliplatin Regimen: 1 cycle Dosage: 130mg/m\^2

dMMR/MSI-H GC

D2 radical gastrectomy PROCEDURE

Curative-intent D2 radical gastrectomy is scheduled 4-6 weeks after completion of the fourth cycle.

dMMR/MSI-H GC

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, aged 18 to 85 years.
• Histologically confirmed gastric cancer or adenocarcinoma of the esophagogastric junction (only Siewert types II and III are included).
• dMMR status confirmed by immunohistochemistry (IHC) or MSI-H status confirmed by PCR/NGS.
• Tumor clinical staging meeting the following criteria:
• cT≥2, any N, M0, assessed by the investigator as potentially resectable and planned for preoperative treatment followed by surgery.
• Willing to receive treatment with immune checkpoint inhibitors (including, but not limited to, various PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, PD-1/CTLA-4 bispecific antibodies, etc.), which may be combined with or without standard chemotherapy regimens for gastric cancer.

You may not qualify if:

• Tumor histology other than adenocarcinoma, such as squamous cell carcinoma, neuroendocrine carcinoma, etc.
• Presence of central nervous system metastases and/or leptomeningeal carcinomatosis.
• Prior antitumor therapy directed at the current gastric cancer (excluding palliative gastrointestinal bypass surgery performed to relieve obstructive symptoms).

Sponsors & Collaborators

• Shanghai Zhongshan Hospital: lead

MeSH Terms

Conditions

Turcot syndrome

Interventions

Immunotherapy; Induction Chemotherapy

Intervention Hierarchy (Ancestors)

Immunomodulation; Biological Therapy; Therapeutics; Drug Therapy; Remission Induction

Central Study Contacts

Zhaoqing Tang

CONTACT

021-64041990; tang.zhaoqing@zs-hospital.sh.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief of Department of Gastrointestinal Surgery

Study Record Dates

• First Submitted: November 19, 2025
• First Posted: December 2, 2025
• Study Start: January 31, 2026
• Primary Completion (Estimated): December 30, 2029
• Study Completion (Estimated): December 30, 2029
• Last Updated: January 7, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share