Abstract
Ripretinib (QINLOCK™) is a novel type II tyrosine switch control inhibitor being developed by Deciphera Pharmaceuticals for the treatment of KIT proto-oncogene receptor tyrosine kinase (KIT)-driven and/or platelet derived growth factor receptor A (PDGFRA)-driven cancers, including gastrointestinal stromal tumour (GIST). Ripretinib inhibits KIT and PDGFRA kinase, including wild-type, primary and secondary mutations, as well as other kinases, such as PDGFRB, TIE2, VEGFR2 and BRAF. In May 2020, oral ripretinib received its first approval in the USA for the treatment of adult patients with advanced GIST who have received prior treatment with ≥ 3 kinase inhibitors, including imatinib. The US FDA, Health Canada and the Australian Therapeutic Goods Administration collaborated on the review of the ripretinib new drug application in this indication as part of Project Orbis; regulatory review in Australia and Canada is ongoing. Clinical development for GIST, solid tumours and systemic mastocytosis is underway in several countries worldwide. This article summarizes the milestones in the development of ripretinib leading to this first approval for the treatment of advanced GIST.
Highlights
Gastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour of the gastrointestinal tract, with a global annual incidence of 10–15 cases per million [1]
Targeted therapy with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of GIST, with imatinib approved for patients with KIT positive unresectable and/ or metastatic malignant GIST, sunitinib for those with imatinib-resistant GIST and regorafenib for patients with imatinib- and sunitinib-resistant GIST [3]
Ripretinib synergized with the MEK inhibitors trametinib and binimetinib in inducing apoptosis in imatinib-sensitive and -resistant GIST and mastocytosis cell lines [9]
Summary
Gastrointestinal stromal tumour (GIST) is the most common mesenchymal tumour of the gastrointestinal tract, with a global annual incidence of 10–15 cases per million [1]. Some patients have primary resistant GIST, and most patients with initial clinical benefit eventually develop resistance due to acquisition of secondary KIT mutations [2, 4]. Submission, MAA Marketing Authorisation Application, PDUFA Prescription Drug User Fee Act, RTOR Real-Time Oncology Review this heterogeneity, an unmet need existed for a drug that inhibited a broad spectrum of KIT and PDGFRA mutants, blocking the various resistance mutations and limiting the impact of further resistance mutations [2, 4]. Ripretinib (QINLOCKTM) is a novel type II, tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in KIT and PDGFRA. It is being developed by Deciphera Pharmaceuticals for the treatment of KIT- and PDGFRA-driven cancers, including GIST, systemic mastocytosis and other solid tumours. Zai Lab received exclusive regional development and commercialization rights for ripretinib in Greater China [7]
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