We performed a single-arm, retrospective study at the First Affiliated Hospital of Sun Yat-sen University.

Patients aged ≥ 18 years with histologically confirmed HER2-negative advanced gastric or GEJ adenocarcinoma were eligible for this retrospective study. All of the patients had experienced disease progression following first-line chemotherapy, which typically consisted of a platinum agent combined with fluoropyrimidine. Additionally, patients were required to have received apatinib combined with irinotecan as second-line treatment after the failure of first-line chemotherapy. Other inclusion criteria included having at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [20] and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. The patients also needed to have normal or controlled blood pressure, and adequate renal, hepatic, and hematopoietic function.

Since this study focused on the efficacy of antiangiogenic therapy in HER2-independent pathways, HER2-positive patients were excluded because HER2-targeted drugs (e.g., trastuzumab) may affect survival outcomes through different biological mechanisms. Patients were excluded if they had a history of treatment with apatinib or irinotecan to avoid bias due to prior drug exposure. Additionally, those with other active malignant tumors at the start of treatment were excluded to ensure that the study's results were specific to the treatment of gastric or GEJ adenocarcinoma. Patients with severe, uncontrolled comorbidities, such as significant cardiovascular, hepatic, or renal impairments, were also excluded to prevent these conditions from influencing the treatment outcomes. Individuals with poor functional status, indicated by an ECOG performance status greater than 1, were excluded to ensure that they had sufficient functional capacity to tolerate the treatment. Other exclusion criteria included clinically significant gastrointestinal abnormalities that could interfere with treatment, a history of psychotropic drug use and an inability to abstain from such drugs, mental disorders, and pregnancy or lactation. Furthermore, patients with a history of myocardial infarction, unstable angina, symptomatic peripheral vascular disease, or class II, III, or IV congestive heart failure (as defined by the New York Heart Association) in the previous 6 months, as well as those with evidence of active bleeding or bleeding diathesis, were also excluded.

The study protocol was approved by the Research Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University and conducted in accordance with the Helsinki Declaration.

Patients with evidence of tumor progression on CT or MRI underwent a pretreatment evaluation, which included medical history review, clinical examinations, and laboratory analyses (complete blood count, serum chemistry, electrocardiography, and urine analysis).

Patients received irinotecan (180 mg/m2 intravenously once every 3 weeks) plus oral apatinib (500 mg once daily on days 1–21 of each 3-week cycle). The treatment was continued until patients experienced disease progression, unacceptable toxicity, or death.

Data on patient demographics, treatment regimens, response rates, progression-free survival (PFS), overall survival (OS), and adverse events were collected from the medical records. Response evaluation was conducted via the RECIST criteria, with imaging performed every two months. The last follow-up date was November 25, 2023. Safety and adverse events were graded and assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).

The primary endpoints were PFS and OS (defined as the time from treatment initiation until death). PFS was defined as the time from the initiation of apatinib plus irinotecan treatment to the first documented progression of the disease or death from any cause. OS was defined as the time from the start of treatment to death from any cause. The secondary endpoints included the objective response rate (ORR), disease control rate (DCR), and safety assessment. The ORR, calculated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was defined as the proportion of patients who achieved a complete response (CR) or partial response (PR). DCR was defined as the proportion of patients who achieved CR, PR, or stable disease (SD).

Progression-free survival and overall survival analyses and associated 95% CIs were estimated via the Kaplan‒Meier method. Survival analyses were performed via univariable and multivariable Cox regression analyses (backward stepwise methods; all factors were included). A P value of < 0.05 indicated statistical significance. Adverse events were graded according to CTCAE v5.0. We used SPSS version 27.0 (IBM Corporation, Armonk, NY, USA) and R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria) for all the statistical analyses, and the figures were created with GraphPad Prism v8.01 (GraphPad Software Inc., USA).

The internal review board and the ethics committee at The First Affiliated Hospital of Sun Yat-sen University approved the study protocol, which is registered with Chictr.org.cn under ChiCTR1900021377. As the collected patient data was sufficiently anonymized, no informed consent was required for data acquisition.