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

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

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.

Study Overview

• Status: Recruiting
• Conditions: KIT Gene Mutation; GIST - Gastrointestinal Stromal Tumor
• Intervention / Treatment: Drug: physician-selected treatment; Drug: Regorafenib + Envafolimab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jian Li, MD; Phone Number: +86 010 88196561; Email: oncogene@163.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100101
      • Recruiting
      • Beijing Cancer Hospital
      • Principal Investigator: Jian Li, MD
      • Contact: Jian Li, MD; Phone Number: +86 010-88196561; Email: oncogene@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: control group（physician-selected）; Physicians will make selections based on previous drug tolerance, genetic types, etc.: 1) Maintenance treatment with the original dose of previously effective TKIs: during the previous treatment, the patient had achieved at least stable disease (SD) or partial response (PR), with progression-free survival (PFS) exceeding 6 months and tolerable adverse reactions; 2) Combination therapy with two TKI targeted drugs: according to different action targets indicated by genetic testing of the patient's tissue or peripheral blood, different drugs will be selected for maintenance, or a combination of previously effective and well-tolerated drugs will be chosen, or combination therapy will be selected with reference to previous tolerance.	Drug: physician-selected treatment; physician-selected treatment
Experimental: treatment group（Regorafenib + Envafolimab）; Patients in the treatment group will receive regorafenib combined with envafolimab. Regorafenib: 120 mg, orally, once daily, administered for 3 weeks followed by 1 week of rest. Envafolimab: 200 mg, subcutaneously injected, once every 2 weeks.	Drug: Regorafenib + Envafolimab; Regorafenib: 120mg, orally, qd, administered for 3 weeks followed by 1 week of rest. Envafolimab: 200mg, subcutaneously injected, q21d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival（PFS）	Defined as the time from date of study treatment to disease progression radiological/clinical or death due to any cause, whichever occurs first.	Up to 2 years

Collaborators and Investigators

• Sponsor: Jian Li
• Investigators: Study Chair: Jian Li, MD, Peking University Cancer Hospital & Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: April 20, 2026
• First Submitted That Met QC Criteria: April 27, 2026
• First Posted (Actual): April 30, 2026

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Treatment; Gastrointestinal Stromal Tumor; kit gene
• Additional Relevant MeSH Terms: Neoplasms; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Skin Diseases; Eye Diseases, Hereditary; Hypopigmentation; Pigmentation Disorders; Skin Diseases, Genetic; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Amino Acid Metabolism, Inborn Errors; Albinism; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Gastrointestinal Stromal Tumors; Piebaldism; regorafenib; envafolimab
• Other Study ID Numbers: GIST006

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No