Abstract
The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.
Highlights
Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal (1, 2); they occur primarily within the stomach (~56%) and small intestine (~32%) but can arise anywhere in the gastrointestinal (GI) tract (3)
KIT/platelet-derived growth factor receptor a (PDGFRA) inhibition remains the backbone of therapy for metastatic GIST due to the underlying oncogenic drivers of this disease
Ripretinib, as a switch-pocket inhibitor may inhibit a broader range of mutations, while avapritinib, a type 1 kinase inhibitor, clearly provides benefit for the previously treatment-resistant PDGFRA D842V mutation
Summary
Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal (1, 2); they occur primarily within the stomach (~56%) and small intestine (~32%) but can arise anywhere in the gastrointestinal (GI) tract (3). The majority of GISTs harbor activating mutations in 1 of 2 receptor tyrosine kinases (RTKs): KIT (approximately 69%–83%) (4),or platelet-derived growth factor receptor a (PDGFRA; approximately 5%–10%) (5, 6). “Wild-type” or preferably non-KIT/PDGFRA-mutant GISTs may have a succinate dehydrogenase complex deficiency (8), or harbor other mutations, such as activating mutations of BRAF or loss-of-function of NF1, that lead to activation of the PI3K/ mTOR and/or the RAS/RAF/MAPK pathways (7, 9, 10). We will discuss how specific classes of mutations have driven the need for newer treatments for GIST and compare historical and next-generation KIT/ PDGFRA kinase inhibitors with a focus on their MOA. The majority of mutations occur in exon 11 (70%–80%), which encodes the juxtamembrane domain, leading to disruption in autoinhibitory function and resulting in increased auto-activation of the kinase (17, 19). Primary mutations are found in exon 13 (which encodes the ATP-binding region) and exon 17 (which encodes the activation loop), with an occurrence of about 1% each and less frequently in exon 8, encoding part of the extracellular domain (4, 17, 19)
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