Gastrointestinal stromal tumors (GISTs) are mostly driven by c-kit or PDGFRA mutations, and commonly occur in the stomach and small intestine. Targeted therapy is the mainstay for advanced metastatic GISTs, but there is a lack of effective regimens after drug resistance. Immune checkpoint inhibitors (ICIs) have limited efficacy as monotherapy, while tyrosine kinase inhibitor (TKI) drugs such as regorafenib can improve the immune microenvironment and exert a synergistic effect when combined with ICIs, with more significant efficacy especially in cases with kit exon 17 mutations. This study aims to explore the effectiveness of regorafenib combined with envafolimab in metastatic gastrointestinal stromal tumors with kit exon 17 mutations that have failed standard treatment.

This is a multicenter, prospective phase II clinical study aiming to explore the efficacy and safety of regorafenib combined with envafolimab in metastatic gastrointestinal stromal tumors (GIST) with KIT exon 17 mutations that have failed standard treatment, as well as to investigate the correlation between the immune microenvironment and the efficacy of immunotherapy.

The study will enroll patients with histologically confirmed advanced metastatic GIST harboring KIT exon 17 mutations, with at least one evaluable lesion. Patients will be randomized at a 1:1 ratio into two groups: the experimental group will receive regorafenib combined with envafolimab (regorafenib at a recommended dose of 120 mg orally once daily, administered for 3 weeks followed by 1 week off; envafolimab 200 mg subcutaneously injected once every 2 weeks); the control group will receive either re-challenge with one previously effective targeted agent or combination therapy with two agents selected based on the clinician's experience. Treatment will continue until disease progression, occurrence of intolerable toxicity, or voluntary withdrawal of the patient from the trial.

A total of 100 patients are planned to be enrolled. Enrolled patients will undergo imaging assessments at baseline and every 2 months during treatment.

Inclusion Criteria:

• Aged ≥ 18 years, regardless of gender;
• Confirmed as gastrointestinal stromal tumor by histopathological examination;
• Having at least one measurable target lesion meeting the criteria of mRECIST v1.1 (non-lymph node lesions with a long axis ≥ 1.0 cm or a long axis ≥ the thickness of 2 slides); imaging assessment should be performed within 14 days before the first medication;
• Disease progression or intolerance after treatment with imatinib, sunitinib, regorafenib, or ripretinib;
• Primary or secondary KIT exon 17 mutation detected by genetic testing;
• Sufficient organ and bone marrow function, defined as follows: Blood routine: Absolute neutrophil count (ANC) ≥ 1.5×10⁹/L; platelet count (PLT) ≥ 75×10⁹/L; hemoglobin (HGB) ≥ 9.0 g/dL. No use of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), red blood cell transfusion, or platelet transfusion within 14 days before the examination; Liver and kidney function: For subjects without liver metastasis, serum total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN. For subjects with liver metastasis: TBIL ≤ 1.5×ULN; ALT and AST ≤ 5×ULN. Renal function: Serum creatinine (Scr) ≤ 1.5×ULN; Sufficient coagulation function, defined as international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5×ULN; if the subject is receiving anticoagulant therapy, it is acceptable as long as PT is within the range specified for the anticoagulant drug;
• Provide 15 paraffin-embedded tissue sections before enrollment for immune microenvironment detection;
• ECOG PS score of 0-2;
• Signed informed consent form.

Exclusion Criteria:

• A history of intolerance to regorafenib treatment, or previous receipt of immune checkpoint inhibitor therapy;
• Being in pregnancy or lactation;
• Those with an expected survival period of less than 3 months;
• Those who have undergone major surgery or suffered significant trauma within 4 weeks before the first blood collection during the screening period, or are expected to require major surgery during the study period;
• Patients with current active ulcers or gastrointestinal bleeding;
• A history of interstitial lung disease or non-infectious pneumonia; a history of active tuberculosis;
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage;
• Patients with clinically confirmed autoimmune diseases; those with positive HIV or HCV; those with HBV-DNA exceeding the laboratory normal range; those with acute CMV infection;
• Patients with clinically confirmed central nervous system metastases;
• Patients with other malignant tumors within 5 years;
• Immunosuppressed subjects, including those with known immunodeficiency; those currently receiving systemic steroid medications (except those who have used inhaled steroids recently or currently);
• Uncontrolled hypertension: After active antihypertensive treatment, three consecutive blood pressure measurements indicate systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥ 100 mmHg;
• Subjects who, in the investigator's assessment, are unable or unwilling to comply with the requirements of the study protocol.