Systemic Therapy for Gastrointestinal Stromal Tumor: Current Standards and Emerging Challenges

Area of Science:

• Oncology
• Gastrointestinal Pathology
• Molecular Targeted Therapy

Background:

• Gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the GI tract, often driven by KIT or PDGFRα mutations.
• Surgical resection offers curative potential for localized GIST.
• The advent of tyrosine kinase inhibitors (TKIs) like imatinib, sunitinib, and regorafenib has transformed the management of advanced and metastatic GIST.

Purpose of the Study:

• To review the current landscape of GIST treatment, including established and emerging therapies.
• To highlight the challenges posed by drug resistance and the management of KIT/PDGFRα wild-type GIST.
• To explore potential novel therapeutic targets for improving GIST treatment efficacy.

Main Methods:

• Review of clinical trial data and published literature on GIST management.
• Analysis of the efficacy and limitations of current multi-line TKI therapies.
• Exploration of emerging therapeutic strategies, including immune checkpoint inhibitors and targeting specific signaling pathways.

Main Results:

• Recent approvals of ripretinib and avapritinib expand fourth-line and first-line treatment options, respectively.
• Drug resistance remains a significant obstacle in advanced GIST, limiting long-term disease control.
• KIT/PDGFRα wild-type GISTs exhibit reduced sensitivity to standard TKIs, indicating a need for alternative approaches.
• Early trials suggest moderate responses with immune checkpoint inhibitors in heavily pretreated patients.
• Targeting fibroblast growth factor receptor (FGFR) signaling shows promise for wild-type GIST.

Conclusions:

• Despite advances with TKIs, overcoming drug resistance and treating wild-type GIST remain critical challenges.
• Novel therapeutic targets, including FGFR signaling, represent promising avenues for improving outcomes in GIST.
• Continued research into experimental TKIs and combination therapies is essential for advancing GIST management.