A Study of Disitamab Vedotin, Tunlametinib, and PD-1 Antibody for Advanced Gastric Cancer (DTP-HER2)

A Study on the Efficacy and Safety of Disitamab Vedotin Combined With Tunlametinib and PD-1 Antibody in Third-Line and Above Treatment of Patients With HER2-Overexpressing Advanced Gastric Cancer

The goal of this clinical trial is to learn if the combination of disitamab vedotin, tunlametinib, and a PD-1 antibody works to treat HER2-overexpressing advanced gastric cancer in patients who have already received at least two lines of prior therapy. It will also learn about the safety of this combination therapy.

The main questions it aims to answer are:

What is the objective response rate (tumor shrinkage) in participants receiving this combination? What medical problems (side effects) do participants have when taking this combination? Researchers will evaluate the efficacy and safety of disitamab vedotin combined with tunlametinib and a PD-1 antibody in patients with HER2-overexpressing advanced gastric cancer who have failed at least two lines of standard treatment.

Participants will:

Receive disitamab vedotin intravenously every 2 weeks and a PD-1 antibody intravenously once every 6 weeks.

Take tunlametinib orally every 12 hours. Continue treatment until disease progression or unacceptable toxicity. Visit the clinic every 2 weeks for checkups, blood tests, and safety monitoring.

Undergo tumor imaging assessments every 6 weeks to evaluate treatment response.

Study Overview

• Status: Not yet recruiting
• Conditions: Gastric Adenocarcinoma
• Intervention / Treatment: Drug: Tunlametinib+PD-1 mAb

Detailed Description

This is an open-label, single-arm, phase II clinical trial evaluating the efficacy and safety of disitamab vedotin (RC48) in combination with tunlametinib and a PD-1 antibody (tislelizumab) in patients with HER2-overexpressing advanced gastric cancer who have failed at least two lines of prior systemic therapy.

Background HER2-overexpressing gastric cancer accounts for approximately 12-23% of advanced gastric cancer cases. Disitamab vedotin, a novel anti-HER2 antibody-drug conjugate (ADC) conjugated with the microtubule inhibitor MMAE, has demonstrated an objective response rate (ORR) of 24.8% and a median overall survival (OS) of 7.9 months in third-line treatment of HER2-overexpressing advanced gastric cancer (C008 study). However, primary and acquired resistance to ADC monotherapy remains a significant clinical challenge. Preclinical studies by the study team have shown that MAPK-ERK pathway inhibition with MEK inhibitors can upregulate HER2 expression, enhance lysosomal activity, and synergistically augment the antitumor activity of HER2-ADCs both in vitro and in vivo. The combination of a MEK inhibitor with disitamab vedotin and a PD-1 antibody has demonstrated synergistic effects in humanized mouse models.

Study Design The study consists of a safety run-in phase followed by an expansion phase. The safety run-in phase will evaluate three dose levels of tunlametinib (6 mg, 9 mg, and 12 mg orally every 12 hours) in combination with fixed doses of disitamab vedotin (2.5 mg/kg intravenously every 2 weeks) and tislelizumab (400 mg intravenously every 6 weeks) to determine the recommended dose for the expansion phase.

Following determination of the recommended dose, the expansion phase will enroll additional patients to further evaluate the efficacy and safety of the triplet combination.

Treatment Regimen

Disitamab vedotin (RC48): 2.5 mg/kg intravenously on Day 1 of each 14-day cycle

Tislelizumab: 400 mg intravenously on Day 1 of each 42-day cycle

Tunlametinib: Orally every 12 hours at the dose determined during the safety run-in phase

Treatment will continue until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specified discontinuation criteria are met. Tumor assessments will be performed every 6 weeks ± 3 days using enhanced CT or MRI according to irRECIST criteria.

Study Objectives

Primary Objectives: To evaluate the objective response rate (ORR) and safety profile of the combination therapy

Secondary Objectives: To evaluate progression-free survival (PFS), overall survival (OS), and quality of life

Exploratory Objectives

To analyze HER2 protein expression and immune cell infiltration in pre-/post treatment tumor tissue samples

To assess changes in serum cytokine levels before and after treatment

To characterize gut microbiota composition using 16S and metagenomic sequencing of fecal samples collected at baseline, first efficacy assessment, and disease progression.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Miaozhen Qiu, MD, PhD; Phone Number: 8602087343351; Email: qiumzh@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-Sen University Cancer Center
      • Contact: Miaozhen Qiu, MD, PhD; Phone Number: 8602087343351; Email: qiumzh@sysucc.org.cn
      • Sub-Investigator: Miao-Zhen Qiu, MD, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Patients with advanced gastric cancer who have received at least two lines of prior systemic therapy or are intolerant to standard therapy; HER2 immunohistochemistry (IHC) 2+ or 3+; Presence of measurable target lesions according to irRECIST criteria; Expected survival of at least 3 months; Age ≥ 18 years, male or female;

Adequate organ function meeting the following requirements:

1. White blood cell count (WBC) ≥ 3.0 × 10⁹/L, absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L;
2. Platelet count ≥ 75 × 10⁹/L;
3. Hemoglobin ≥ 9 g/dL;
4. Serum albumin ≥ 2.8 g/dL;
5. Total bilirubin ≤ 1.5 × upper limit of normal (ULN), ALT, AST, and/or ALP ≤ 2.5 × ULN;
6. Serum creatinine ≤ 1.5 × ULN or creatinine clearance > 60 mL/min; Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1; Ability to understand the study and provide written informed consent.

Exclusion Criteria:

Known or suspected hypersensitivity to the investigational drugs. Dysphagia. Female patients who are pregnant or breastfeeding. Patients who have received disitamab vedotin in first- or second-line treatment.

Inability to provide informed consent due to psychological, family, social, or other factors.

Severe impairment of cardiac, pulmonary, hepatic, or renal function; hematopoietic system disorders; cachexia; or other conditions that preclude tolerability of drug therapy.

Autoimmune diseases or history of autoimmune diseases (e.g., colitis, hepatitis, hyperthyroidism, including but not limited to these diseases or syndromes); history of immunodeficiency, including positive HIV test, or other acquired or congenital immunodeficiency diseases; history of organ transplantation or allogeneic bone marrow transplantation.

Patients requiring systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose or during the study period. However, the following circumstances are permitted for enrollment: topical or inhaled steroids, or adrenal hormone replacement therapy at a dose ≤10 mg/day prednisone equivalent, in the absence of active autoimmune disease.

History of interstitial lung disease or non-infectious pneumonitis.

Active pulmonary tuberculosis infection identified by medical history or CT scan, or history of active pulmonary tuberculosis infection within 1 year prior to enrollment, or history of active pulmonary tuberculosis infection more than 1 year prior to enrollment without appropriate treatment.

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: DTP; Disitamab vedotin (RC48): 2.5 mg/kg intravenously on Day 1 of each 14-day cycle Tislelizumab: 400 mg intravenously on Day 1 of each 42-day cycle Tunlametinib: Orally every 12 hours at the dose determined during the safety run-in phase	Drug: Tunlametinib+PD-1 mAb; Disitamab vedotin (RC48): 2.5 mg/kg intravenously on Day 1 of each 14-day cycle Tislelizumab: 400 mg intravenously on Day 1 of each 42-day cycle Tunlametinib: Orally every 12 hours at the dose determined during the safety run-in phase; Other Names: Disitamab vedotin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Objective response rate is defined as the proportion of participants who achieve a best overall response of either complete response (CR) or partial response (PR) according to irRECIST (immune-related Response Evaluation Criteria in Solid Tumors) criteria.	Up to approximately 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Time from first dose of study treatment to death from any cause. Participants alive at the time of analysis will be censored at the last known alive date. Kaplan-Meier method will be used to estimate median OS with 95% confidence intervals.	Up to 24 months after last patient enrollment
Progression free survival	Progression-free survival is defined as the time from the first dose of study treatment to the date of first documented disease progression per irRECIST criteria or death from any cause, whichever occurs first.	Up to approximately 24 months

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Collaborators: RemeGen Co., Ltd.; Shanghai Kechow Pharma, Inc.; BeOne Medicines

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: March 26, 2026
• First Submitted That Met QC Criteria: March 26, 2026
• First Posted (Actual): April 2, 2026

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: immunotherapy; MEK; HER2 overexpression; HER2-ADC
• Additional Relevant MeSH Terms: disitamab vedotin
• Other Study ID Numbers: SYSUCC-HER2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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