New drugs in gastrointestinal stromal tumors

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Gastrointestinal stromal tumors (GIST) are primarily treated with tyrosine kinase inhibitors (TKIs).
• Mutations in KIT and PDGFRα drive GIST development and resistance to therapies.
• Understanding these mutations has led to the development of novel, targeted compounds.

Purpose of the Study:

• To review the latest advancements in the treatment of advanced gastrointestinal stromal tumor (GIST) patients.
• To highlight new tyrosine kinase inhibitors (TKIs) developed to overcome treatment resistance in GIST.
• To summarize the efficacy of novel TKIs in preclinical and clinical settings.

Main Methods:

• Review of preclinical studies and clinical trials involving novel TKIs for GIST.
• Analysis of the mechanisms of action for new agents targeting KIT and PDGFRα mutations.
• Summary of current treatment standards and emerging therapeutic strategies.

Main Results:

• Ripretinib, a type II inhibitor, is effective in fourth-line advanced GIST treatment.
• Avapritinib, a type I inhibitor, shows significant activity against the D842V mutation, a previously resistant form.
• Crenolanib, a selective type I inhibitor, targets PDGFRα-resistant mutants, including D842V, and is in clinical trials.

Conclusions:

• Novel TKIs like ripretinib and avapritinib represent significant progress in advanced GIST therapy.
• Targeted therapies are emerging as effective options for specific GIST mutations, including resistant ones.
• Future treatment landscapes may include MEK inhibitors, immunotherapy, and TRK-targeted therapy for select GIST patients.