Study Population:Patients with locally advanced gastric cancer complicated by hypertension, who are scheduled to undergo laparoscopic gastric cancer resection after receiving preoperative immunotherapy.
Primary Objective: To investigate the impact of combined beta-blocker use on the efficacy of immunotherapy in patients with locally advanced gastric cancer.
Secondary Objective: To investigate the impact of combined beta-blocker use on the incidence of immune-related adverse events.
Study Groups:This study does not include a parallel control group; it enrolls only a single study group.
Study Design:This is a single-arm, exploratory clinical study. Study Duration:2026 - 2029 Sample Size: Single-arm, exploratory trial, planned enrollment of 33 cases.
Inclusion Criteria:
* Voluntarily sign the informed consent form; * Aged 18-75 years; * ECOG performance status 0-1; * Either sex; * Patients with a standardized histopathological diagnosis of gastric adenocarcinoma from the primary gastric lesion via endoscopic biopsy, according to the 15th edition of the Japanese Classification of Gastric Carcinoma (2017); * Patients judged by the treating physician to require preoperative immune checkpoint inhibitor therapy, followed by potentially curative gastrectomy; * Meet the diagnostic criteria for hypertension according to the 2023 Chinese Guidelines for the Management of Hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, or a previous diagnosis of uncontrolled hypertension), with an indication for beta-blocker use; * Deemed by a specialist to have no contraindications for beta-blocker use and can use beta-blockers for antihypertensive therapy.
Exclusion Criteria
* HER2-positive or microsatellite instability-high (MSI-H)/dMMR gastric cancer confirmed by immunohistochemistry; * Active autoimmune disease requiring continuous immunosuppressive therapy or history of transplantation; * Currently receiving systemic immunosuppressive medication: If a patient is currently using corticosteroids, the corticosteroid dose must be ≤ equivalent of prednisone 10 mg daily; * History of (non-infectious) pneumonitis/interstitial lung disease requiring treatment; * Concurrent infection with human immunodeficiency virus (HIV); * Pregnant or breastfeeding women; * History of psychiatric disorders; * Concurrent other malignancies or severe organ dysfunction; * Presence of contraindications for beta-blocker use (e.g., severe bradycardia, uncontrolled depression, unstable angina, uncontrolled heart failure (Class III or IV), hypotension (systolic blood pressure \<100 mmHg), severe asthma or chronic obstructive pulmonary disease (COPD), symptomatic peripheral arterial disease or Raynaud's syndrome, untreated pheochromocytoma, etc.); * Refractory hypertension; * Judged by the investigator as not meeting the inclusion criteria for this study.
Effectiveness Analysis Primary Endpoint: Proportion of patients with Tumor Regression Grade (TRG) \< 3 (AJCC criteria).
Secondary Endpoints: 3-year overall survival (OS), 3-year progression-free survival (PFS); correlation with immunotherapy-related biomarkers (e.g., PD-L1 expression, cortisol, adrenocorticotropic hormone, tumor tissue ADRB1 expression, tumor tissue RNA sequencing, tumor immune microenvironment); treatment compliance (immunotherapy completion rate, surgery delay rate).
Safety Analysis:Incidence and severity of adverse events. Statistical Analysis:This is an exploratory, single-arm, uncontrolled study. The pathological response rate is the primary evaluation indicator, with a planned enrollment of 33 cases. The sample size was calculated based on the single-sample rate estimation method. Referring to similar exploratory immunotherapy combination studies and considering clinical practice, the anticipated pathological response rate is 80%. Using a two-sided α=0.05 (95% confidence level) and the Clopper-Pearson exact method, the two-sided 95% confidence interval for 33 samples is \[0.625, 0.918\], with an interval width of 0.294, which meets the core objective of preliminarily verifying the efficacy trend of the "standard immunotherapy + beta-blocker" regimen. A 10% dropout rate is also accounted for, balancing recruitment feasibility with basic statistical estimation precision. Descriptive statistical analysis will be used to calculate point estimates and 95% confidence intervals for primary and secondary endpoints. Survival analysis will use the Kaplan-Meier method to plot 3-year OS and PFS curves.
Follow-up:Follow-up will be conducted at 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, and 36 months post-surgery.
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Single group
Experimental Group
DrugSubjects in the experimental group will start taking metoprolol succinate extended-release tablets 47.5 mg (one tablet) once daily, starting from Day 1 of the first cycle of preoperative neoadjuvant immunotherapy, and continue until the day before surgery.
Pathological response of TRG3
Pathological response is assessed on the surgical resection specimen obtained approximately 1 week after completion of neoadjuvant therapy. Tumor regression grade (TRG) is evaluated according to the American Joint Committee on Cancer (AJCC) 8th edition criteria. Pathological non-response is defined as TRG 3, which corresponds to \>50% viable tumor cells remaining in the tumor bed. The primary efficacy endpoint is the pathological response rate, defined as the proportion of patients achieving TRG 0-2 (≤50% residual viable tumor cells). The incidence of TRG 3 (non-response) will be reported descriptively. All pathological evaluations are performed by an experienced gastrointestinal pathologist.
3-year overall survival (OS)
Overall survival (OS) is defined as the time from the start of study treatment (first dose of neoadjuvant immunotherapy) to death from any cause. For patients who are alive at the time of analysis or lost to follow-up, OS will be censored at the last known date the patient was alive. The 3-year OS rate will be estimated using the Kaplan-Meier method, with corresponding 95% confidence intervals. This endpoint will be assessed during follow-up visits scheduled at 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, and 36 months post-surgery. OS is a secondary efficacy endpoint.
3-year progression-free survival (PFS)
Progression-free survival (PFS) is defined as the time from the start of study treatment (first dose of neoadjuvant immunotherapy) to the first documented disease progression (radiographic or clinical) or death from any cause, whichever occurs first. Disease progression is assessed using RECIST criteria (or as per standard clinical practice) during follow-up. For patients who are alive without progression at the time of analysis or lost to follow-up, PFS will be censored at the last evaluable disease assessment. The 3-year PFS rate will be estimated using the Kaplan-Meier method, with corresponding 95% confidence intervals.
Correlation with immunotherapy-related biomarkers
This exploratory endpoint evaluates associations between baseline and post-treatment biomarker levels and clinical outcomes (e.g., pathological response, survival). Biomarkers to be assessed include: Tissue biomarkers: PD-L1 expression (CPS), ADRB1 expression, tumor immune microenvironment profiling (by immunohistochemistry or RNA sequencing) from pre-treatment biopsy and post-surgical resection specimens. Circulating biomarkers: Serum cortisol, adrenocorticotropic hormone (ACTH) levels collected at baseline and prior to surgery.
Pathological response of MPR
Major pathological response (MPR) is defined as the proportion of patients with ≤10% residual viable tumor cells in the surgically resected primary tumor following neoadjuvant therapy. MPR is assessed on the surgical specimen obtained approximately 1 week after completion of preoperative treatment. Pathological evaluation is performed according to standardized tumor regression grading (TRG) systems, with MPR corresponding to TRG 0-1 per AJCC 8th edition criteria (i.e., complete response or minimal residual disease). This endpoint will be reported descriptively with point estimate and 95% confidence interval.
Incidence of treatment-related adverse events
Treatment-related adverse events (AEs) will be assessed from the time of informed consent through 30 days after the last dose of the study drug. AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Safety evaluations will include monitoring of vital signs (blood pressure, heart rate), laboratory tests (complete blood count, electrolytes, liver and kidney function), electrocardiograms, and clinical assessments. Specific AEs of interest include beta-blocker-related events (bradycardia, hypotension) and chemotherapy-related events (neutropenia, thrombocytopenia, hand-foot syndrome). The incidence, severity, and relationship to study treatment will be summarized descriptively for all subjects who receive at least one dose of the investigational drug (Safety Analysis Set).
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