A Study of Regorafenib Combined With Envafolimab for Metastatic Gastrointestinal Stromal Tumors With Kit Gene Exon 17 Mutation That Failed Standard Treatment

A Phase II, Open-label, Multicenter, Randomized Controlled Clinical Trial Comparing Regorafenib Combined With Envafolimab to Physician's Choice in Patients With Metastatic Gastrointestinal Stromal Tumors Harboring KIT Exon 17 Mutations Refractory to Standard Treatment.

This study is a multicenter, prospective, randomized controlled Phase II clinical trial. The primary endpoint is to evaluate the efficacy and safety of regorafenib combined with envafolimab compared to physician's choice in patients with metastatic gastrointestinal stromal tumors harboring KIT exon 17 mutations who have failed standard treatments.

This multicenter, prospective, randomized, controlled phase II clinical trial aims to explore the efficacy and safety of regorafenib combined with envafolimab in treating metastatic GIST with KIT exon 17 mutation that has failed standard treatment. It also seeks to investigate the correlation between the immune microenvironment and the efficacy of immunotherapy.

The study includes patients with histologically confirmed advanced metastatic GIST containing the KIT exon 17 mutation, requiring at least one evaluable lesion. Using a block randomization method, the study is open-label and assigns patients to either the treatment group or the control group in a 1:1 ratio. The treatment group receives regorafenib combined with envafolimab, while the control group continues physician's choice until disease progression, intolerable toxicity, or voluntary withdrawal from the trial.

The governing principle for physician decision-making in the control group was selection based on prior medication tolerability, genotype, etc.:

1. Continued maintenance therapy with the originally effective TKI at the same dose: The patient achieved at least stable disease (SD) or partial response (PR) during prior treatment, with progression-free survival (PFS) exceeding 6 months, and the adverse reactions were tolerable.
2. Combination therapy with two TKIs: Different drugs were selected for maintenance based on distinct actionable mutations identified in the patient's tissue or peripheral blood genetic testing, OR a combination of drugs previously effective and well-tolerated was used, OR the combination therapy was chosen by referencing past tolerability.

A total of 100 patients are planned to be enrolled, with imaging assessments conducted at baseline and every two months during treatment.

Inclusion Criteria:

• Age ≥ 18 years, no gender restriction;
• Pathologically confirmed gastrointestinal stromal tumor (GIST);
• At least one measurable target lesion according to mRECIST v1.1 criteria (non-lymph node lesion with a long axis ≥ 1.0 cm or long axis ≥ 2 slide thicknesses); imaging assessment within 14 days before the first dose;
• Progression or intolerance after treatment with imatinib, sunitinib, regorafenib, or ripretinib;
• Genetic testing includes primary or secondary KIT exon 17 mutation;
• Adequate organ and bone marrow function, defined as follows:

Hematology: Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; platelet count (PLT) ≥ 75 × 10^9/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 testing; Liver and kidney function: For patients without liver metastasis, total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. For patients with liver metastasis: TBIL ≤ 1.5 × ULN; ALT and AST ≤ 5 × ULN. Kidney function: serum creatinine (Scr) ≤ 1.5 × ULN; Adequate coagulation function, defined as international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; if the patient is on anticoagulant therapy, PT should be within the intended range of the anticoagulant;

• Provide 15 paraffin-embedded tissue sections before enrollment for immune microenvironment testing;
• ECOG PS score 0-2;
• Signed informed consent.

Exclusion Criteria:

• Unable to tolerate previous regorafenib treatment or previously received immune checkpoint inhibitors;
• Pregnant or breastfeeding;
• Expected survival less than 3 months;
• Underwent major surgery or experienced significant trauma within 4 weeks before the first blood draw during the screening period, or expected to need major surgery during the study;
• Currently have active ulcers or gastrointestinal bleeding;
• History of interstitial lung disease or non-infectious pneumonia; history of active tuberculosis;
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage;
• Clinically diagnosed autoimmune disease; HIV or HCV positive; HBV-DNA exceeding laboratory normal range; acute CMV infection;
• Patients with central nervous system metastasis;
• Patients with other malignancies within the past five years;
• Immunosuppressed subjects, including those with known immunodeficiency; currently using systemic steroids (except for recent or current use of inhaled steroids);
• Uncontrolled hypertension: Despite aggressive antihypertensive therapy, sequential measurements show systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg on three consecutive occasions;
• Subjects deemed by the investigator to be unable or unwilling to comply with the study protocol requirements.