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Updated: Nov 15, 2025
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Emerging drugs for the treatment of gastrointestinal stromal tumors
Daniel F Pilco-Janeta1, Alfonso García-Valverde1, David Gomez-Peregrina1
1Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital Campus, Barcelona, Spain.
Introduction:
Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial event in gastrointestinal stromal tumor (GIST) biology. Seminal works during the past two decades have underscored, first, the continuous relevance of KIT/PDGFRA oncogenic signaling after progression to targeted inhibition; second, the heterogeneity of KIT/PDGFRA acquired mutations, that cannot be efficiently suppressed by any given tyrosine kinase inhibitor (TKI); and third, the presence of specific mutants highly resistant to all approved therapies.
Areas Covered:
This review discusses treatment options in advanced/metastatic GIST, including a detailed dissection of ripretinib and avapritinib, the two novel small molecule inhibitors approved by the Food and Drug Administration in 2020.
Expert Opinion:
The three only therapeutic options since 2012 for metastatic GIST patients were imatinib, sunitinib, and regorafenib. Although imatinib was highly effective in treatment-naïve GIST, the benefit of second- and third-line sunitinib and regorafenib was modest, thus emphasizing the medical need for new treatment options. Ripretinib, a switch control inhibitor with broad anti-KIT/PDGFRA activity, has been approved as ≥4th line in GIST after progression to all standard therapies. Avapritinib, a type I TKI highly specific against the multi-resistant PDGFRA D842V mutation, is approved in this specific subset of GIST patients.
Insights
New treatments ripretinib and avapritinib offer hope for advanced gastrointestinal stromal tumors (GIST) patients. These novel therapies target specific KIT/PDGFRA mutations, addressing resistance to prior treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gastrointestinal stromal tumors (GIST) are driven by oncogenic KIT or PDGFRA receptor tyrosine kinases.
- Acquired mutations in KIT/PDGFRA lead to resistance against targeted therapies, highlighting unmet needs in advanced GIST treatment.
- Existing therapies like imatinib, sunitinib, and regorafenib show limited efficacy in later treatment lines.
Purpose of the Study:
- To review current treatment options for advanced/metastatic GIST.
- To analyze the efficacy and approval of novel small molecule inhibitors, ripretinib and avapritinib.
- To discuss the role of these new agents in managing GIST with resistant mutations.
Main Methods:
- Review of scientific literature and clinical trial data on GIST treatments.
- Analysis of approved tyrosine kinase inhibitors (TKIs) including ripretinib and avapritinib.
- Discussion of treatment strategies based on mutation profiles and prior therapy lines.
Main Results:
- Ripretinib, a switch control inhibitor, is approved for fourth-line treatment in GIST.
- Avapritinib, a type I TKI, is approved for GIST patients with the PDGFRA D842V mutation.
- These novel agents address specific resistance mechanisms and improve therapeutic options.
Conclusions:
- Ripretinib and avapritinib represent significant advancements in managing advanced/metastatic GIST.
- Targeted therapies are crucial for overcoming KIT/PDGFRA mutation-driven resistance.
- Further research is needed to optimize sequencing and combination strategies for GIST treatment.
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