Factors Influencing Immunotherapy Response in dMMR/MSI-H Gastric/Gastroesophageal Junction Adenocarcinoma (Pre-CATALIS)

Factors Influencing Immunotherapy Response in Mismatch Repair Deficiency (dMMR) / Microsatellite Instability-High (MSI-H) Gastric/Gastroesophageal Junction Adenocarcinoma

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Immunotherapy; Mismatch Repair Deficient or MSI-High Solid Tumors; Gastric / Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Procedure: D2 radical gastrectomy; Drug: Immunotherapy; Drug: Induction chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhaoqing Tang; Phone Number: 021-64041990; Email: tang.zhaoqing@zs-hospital.sh.cn

Participation Criteria

Eligibility Criteria

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

Study Population

All subjects who meet the inclusion and exclusion criteria will be included in the analysis.

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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).

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: dMMR/MSI-H GC; Immunotherapy with induction chemotherapy

Procedure: D2 radical gastrectomy; Curative-intent D2 radical gastrectomy is scheduled 4-6 weeks after completion of the fourth cycle.; Drug: Immunotherapy; 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.; Drug: Induction chemotherapy; Drug: Oxaliplatin Regimen: 1 cycle Dosage: 130mg/m^2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Pathological Response Rate	The proportion of subjects with residual viable tumor cells accounting for <10% of the surgical specimen from the primary tumor site.	From the initiation of treatment to the date of surgery, an average of 14 weeks.
ypN stage	Lymph-node status after neoadjuvant therapy (ypN stage) will be assessed according to the American Joint Committee on Cancer (AJCC) 8th edition staging system.	From the initiation of treatment to the date of surgery, an average of 14 weeks.
R0 resection rate	The proportion of patients who undergo surgery with microscopically negative resection margins.	From the initiation of treatment to the date of surgery, an average of 14 weeks.
Event-free Survival	The time from the subject's enrollment until disease progression, disease recurrence, or death from any cause.	The time from the initiation of treatment until disease progression, disease recurrence, death from any cause, or 3 years since enrollment.
Overall Survival	The time from the subject's enrollment until death from any cause.	From the initiation of treatment until death from any cause or 3 years since enrollment.

Collaborators and Investigators

• Sponsor: Shanghai Zhongshan Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 31, 2026
• Primary Completion (Estimated): December 30, 2029
• Study Completion (Estimated): December 30, 2029

Study Registration Dates

• First Submitted: November 19, 2025
• First Submitted That Met QC Criteria: November 26, 2025
• First Posted (Estimated): December 2, 2025

Study Record Updates

• Last Update Posted (Actual): January 7, 2026
• Last Update Submitted That Met QC Criteria: January 2, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Turcot syndrome; Therapeutics; Drug Therapy; Biological Therapy; Immunomodulation; Remission Induction; Immunotherapy; Induction Chemotherapy
• Other Study ID Numbers: B2025-541R

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Informed consent forms did not include provisions for public data sharing

Drug and device information, study documents

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