Gastrointestinal stromal tumours most often harbour oncogenic mutations in receptor tyrosine kinase proto-oncogene, receptor tyrosine kinase (KIT), or platelet-derived growth factor receptor α (PDGFRA).1, 2 Standard treatment for patients with locally advanced metastatic gastrointestinal stromal tumours are KIT and PDGFRA-directed tyrosine-kinase inhibitors (TKIs).3, 4, 5 First-line treatment with imatinib for patients with advanced gastrointestinal stromal tumours results in response or tumour control in more than 80% of patients.2, 3 However, approximately 50% of patients with advanced gastrointestinal stromal tumours have progressive disease by 24 months and estimated 10-year progression-free survival is around 9%.3, 6, 7 Progressing metastases often harbour secondary mutations in the ATP-binding domain or activation loop of KIT, which represent a major mechanism of resistance to TKIs.8, 9, 10 Both sunitinib and regorafenib, approved for second-line (sunitinib) and third-line (regorafenib) treatment for advanced gastrointestinal stromal tumours, inhibit some of these resistance mutations,11, 12 but neither drug covers the full spectrum of possible mutations,12, 13 yielding a median progression-free survival of 5·6 months for sunitinib and 4·8 months for regorafenib.4, 14, 15, 16 Avapritinib is only approved for gastrointestinal stromal tumours with PDGFRA exon 18 mutations, which account for approximately 6% of the overall population of patients with gastrointestinal stromal tumours.17, 18, 19
Research in context
Evidence before this study
We searched PubMed for articles published in English between January 1, 2005, and January 1, 2020, using the terms “gastrointestinal stromal tumor” or “GIST” combined with “KIT” or “PDGFRA”. Data from studies show that approved TKIs do not fully cover these secondary resistance mutations, leading to suboptimal efficacy results for progression-free survival and overall survival with second-line and third-line therapies. Patients who had disease progression on approved TKIs (ie, imatinib, sunitinib, regorafenib, or avapritinib [avapritinib is only approved for gastrointestinal stromal tumours with PDGFRA exon 18 mutations]) had no other approved treatment options, creating a high unmet clinical need.
Added value of this study
Our study results showed efficacy of ripretinib as a fourth or further line therapy in patients with advanced gastrointestinal stromal tumours, in terms of a significant improvement in median progression-free survival compared with the group receiving placebo. To our knowledge, ripretinib is the first agent to show an improvement in progression-free survival of such magnitude and a median overall survival above 15 months in this patient population. Ripretinib was also generally well tolerated and associated with an acceptable safety profile.
Implications of all the available evidence
Our results showed the clinical activity of ripretinib as fourth-line (or further line) therapy in patients with advanced gastrointestinal stromal tumours. In May, 2020, the US Food and Drug Administration approved ripretinib for the treatment of adult patients with advanced gastrointestinal stromal tumours who have received previous treatment with three or more kinase inhibitors, including imatinib.
Ripretinib (DCC-2618) is a switch-control TKI that broadly inhibits KIT and PDGFRA kinase signalling through a dual mechanism of action.20 Ripretinib specifically and durably binds to both the switch pocket and the activation loop to lock the kinase in the inactive state, preventing downstream signalling and cell proliferation. This dual mechanism of action provides broad inhibition of KIT and PDGFRA kinase activity, including for wild-type KIT and PDGFRA mutations and multiple primary and secondary mutations associated with drug-resistant gastrointestinal stromal tumours.
In in-vitro enzyme assays, ripretinib inhibited platelet-derived growth factor receptor β (PDGFRB), angiopoietin-1 receptor (TIE2), vascular endothelial growth factor receptor 2 (VEGFR2), and serine and threonine-protein kinase B-raf (BRAF), among other kinases.20
A first-in-human, phase 1 study in patients with gastrointestinal stromal tumours or other advanced solid tumours determined the recommended phase 2 dose of ripretinib as 150 mg once daily, which was associated with a favourable tolerability profile and was active in patients with advanced gastrointestinal stromal tumours that were refractory to multiple previous TKIs. Notably, doses of ripretinib 150 mg twice daily were well tolerated without clinically meaningful dose-limiting side-effects.21 In this phase 3 INVICTUS study, we aimed to evaluate the safety and efficacy of ripretinib as fourth-line therapy (or further-line therapy) versus placebo in patients with advanced gastrointestinal stromal tumours.