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.

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.

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.