Efficacy and Safety of Beta-Blockers Combined With Neoadjuvant Immunotherapy for Locally Advanced Gastric Cancer: an Open-lable, Single-arm Study
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Pathological response of TRG3
研究概览
简要总结
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.
详细描述
1. Research Background
- Disease Burden of Gastric Cancer and Current Treatment Challenges
Gastric carcinoma (GC) is one of the most common malignant tumors globally, ranking fifth in incidence and fourth in mortality worldwide. Gastric cancer patients in China often present with advanced stage at diagnosis. Many are already at a progressive or advanced stage upon diagnosis, resulting in short survival times and poor quality of life. In recent years, tumor immunotherapy, particularly immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors), has brought new hope for gastric cancer treatment. These therapies work by relieving the suppression of immune cells by the tumor and activating the patient's own anti-tumor immune response, demonstrating significant efficacy in some gastric cancer patients. However, clinical practice indicates that only about 10%-15% of gastric cancer patients achieve long-term benefit from existing immunotherapy; the majority still face primary or acquired resistance [1]. This situation of low response rates has driven in-depth research into the immunosuppressive mechanisms within the tumor microenvironment [2] and the search for combination strategies that can enhance the effectiveness of immunotherapy. 2. The Core Role of Sympathetic Nervous System Regulation in the Tumor Microenvironment
With advances in tumor immunology, the role of the sympathetic nervous system in the tumor microenvironment is gradually being revealed. Clinical observations have found that gastric cancer patients with baseline anxiety (GAD-7 ≥5) or depression (PHQ-9 ≥5) have a significantly lower rate of achieving pathological significant response (TRG 0-2) after immunotherapy. The core driving factor is the chronic stress state reflected by anxiety-including the physiological and psychological stress from the disease itself and treatment-related anxiety-rather than the anxiety symptoms themselves. When the body is in this state, the sympathetic nervous system is overactivated, releasing large amounts of catecholamine neurotransmitters (primarily norepinephrine and epinephrine), initiating the classic "fight-or-flight" response. In the tumor environment, this response becomes a key driver of immunotherapy resistance by regulating immune function.
Basic research has confirmed that catecholamines elevated by chronic stress play a critical role in tumor immune evasion by binding to β-adrenergic receptors (ADRBs) on the surface of immune cells, particularly the ADRB1 and ADRB2 subtypes highly expressed on CD8⁺ T cells [3]. Specifically, the binding of catecholamines to ADRB1/ADRB2 activates the downstream cAMP/PKA signaling pathway, which, on one hand, inhibits metabolic reprogramming of CD8⁺ T cells (reducing glucose uptake and glycolysis), and on the other hand, promotes the expression of exhaustion markers like PD-1, forming a positive feedback loop [2, 3]. This leads to severe suppression of T cell function, manifested as impaired cell proliferation, reduced secretion of effector molecules (e.g., perforin, granzyme B), and impaired immune memory formation. Ultimately, this results in T cell "exhaustion," rendering them unable to effectively respond to the activation signals of immune checkpoint inhibitors. This is the core biological mechanism underlying the difference in immunotherapy efficacy between patients with and without anxiety [3, 14].
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Given the single-arm design with no requirement for inter-group comparison, blinding for pathologists, radiologists, and follow-up evaluators will not be implemented.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Experimental group
Subjects 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.
干预措施: Experimental Group (Drug)
结局指标
主要结局
Pathological response of TRG3
时间窗: From completion of neoadjuvant therapy to surgical resection; assessed on postoperative pathological specimen approximately 1 week after surgery, up to 4 months after study treatment initiation.
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.
次要结局
- 3-year overall survival (OS)(From the start of study treatment (first dose of neoadjuvant immunotherapy) to death from any cause, assessed up to 36 months post-surgery. The 3-year OS rate is measured at 36 months after surgery.)
- 3-year progression-free survival (PFS)(From start of study treatment to the first documented disease progression or death, assessed up to 36 months post-surgery. The 3-year PFS rate is measured at 36 months after surgery.)
- Correlation with immunotherapy-related biomarkers(Pre-treatment tumor biopsy at baseline; blood samples at baseline and before surgery (approximately 4 months); post-treatment tumor tissue from surgical resection specimen (approximately 1 week after surgery).)
- Pathological response of MPR(From completion of neoadjuvant therapy to surgical resection; assessed on postoperative pathological specimen approximately 1 week after surgery, up to 4 months after study treatment initiation.)