Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib

Introduction: Discovery of oncogenic mutations in the KIT and PDGFRA tyrosine kinase receptor was a crucial step for the development of tyrosine kinase inhibitors (TKIs). Since then, GIST became a model for the development of molecular-targeted therapy, which led to dramatically improved median overall survival of advanced GIST. Still, further progress is needed after third-line or for TKI resistant mutations. Areas covered: In this review, after a brief introduction on imatinib, sunitinib, and regorafenib, an overview of TKIs that was evaluated beyond these drugs is provided, with a main focus on the novel approved TKIs. Expert opinion: Combination therapies have thus far not fulfilled their promise in GIST, nor did immunotherapy. Increased understanding of GIST and advances in the development of molecular-targeted drugs led to the introduction of ripretinib and avapritinib. Furthermore, NTRK inhibitors became available for ultrarare NTRK fusions. Solutions for NF1 and BRAF mutated and SDH-deficient GIST are still to be awaited. This all underlines the need for adequate molecular profiling of high-risk GISTs before treatment is started. Possibly by using circulating tumor DNA in the future, targeting resistance mutations with specific drugs along the course of the disease would be easier, avoiding multiple tumor biopsies.

Automated summary

The discovery of oncogenic mutations in the KIT and PDGFRA tyrosine kinase receptor was a crucial step in the development of tyrosine kinase inhibitors (TKIs). GIST became a model for molecular-targeted therapy, leading to improved overall survival, but further progress is needed for TKI resistant mutations. Combination therapies and immunotherapy have not fully delivered on their promise in GIST. The development of novel approved TKIs like ripretinib and avapritinib, as well as NTRK inhibitors for ultrarare NTRK fusions, highlight the ongoing need for adequate molecular profiling of high-risk GISTs before treatment.