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

Abstract

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 moleculartargeted 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.

Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

“…However, the addition of ripretinib and avapritinib to our therapeutic armamentarium challenges this algorithm [ 19 , 20 ] ( Table 2 ). Imatinib is a TKI that works by binding to the ATP binding sites on CD117 and PDGFRA, which leads to a block of signal transduction.…”

Genomic Characterization of Radiation-Induced Intracranial Undifferentiated Pleomorphic Sarcoma

“…Our results overlapped with some of these existing data, discussed as follows. Somatic activating mutations in KIT and PDGFRA have been well-described and are mutually exclusive in gastrointestinal stromal tumors [20,21], leading to the approval of the tyrosine kinase inhibitors, imatinib, sunitinib, and regorafenib for these rare tumors [22]. Activating KIT mutations are also prevalent in a subset of melanoma, and…”

Ripretinib in treatment of repeatedly relapsing rectal gastrointestinal stromal tumor: a case report

“…But, further progress is needed after third-line or for TKI resistant mutations. The current second-line and third-line drugs are not good enough in the treatment of mutations in the active ring region, and the objective response rate is very low in patients with failed imatinib treatment (2).…”