Targeting the Unmet Need in Gastrointestinal Stromal Tumors: A Contemporary Review of Investigational Clinical Trials and Therapeutic Landscape

Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are primarily driven by activating mutations in KIT or PDGFRA. Although tyrosine kinase inhibitors (TKIs), particularly imatinib, have substantially improved outcomes, most patients with advanced disease eventually develop resistance, resulting in disease progression. Methods: We performed a narrative review with scoping approach of interventional clinical trials registered on ClinicalTrials.gov between January 2020 and July 2025 to characterize the contemporary investigational therapeutic landscape in GIST. Eligible studies included clinical trials evaluating novel agents, combinations, or alternative strategies beyond current regulatory approvals. Trial characteristics, therapeutic classes, endpoints, enrollment, and funding sources were analyzed. Results: A total of 27 ongoing trials were identified. Most studies were phase I/II and focused on metastatic or unresectable disease, predominantly in the second-line or later settings. TKIs remained the dominant therapeutic class, included in over 70% of trials, either as monotherapy or in combination. Emerging strategies comprised antibody–drug conjugates, immune checkpoint inhibitors, HIF inhibitors, FGFR inhibitors, and epigenetic modulators. Only four phase III trials were identified, reflecting the difficulty of conducting large, randomized studies in GIST. No trial used overall survival or quality of life as a primary endpoint. Conclusions: The current investigational landscape in GIST is largely focused on overcoming TKI resistance in advanced disease. Molecular stratification and personalized approaches dominate ongoing research, but evidence generation remains limited by small sample sizes and slow recruitment. Future trials integrating innovative therapeutic platforms and patient-centered outcomes are essential to improve long-term disease control and quality of life.