Abstract
BackgroundThe majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.MethodsThis Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.ResultsSixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.ConclusionsBuparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.Trial registration numberNCT01468688.
Highlights
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients
A major challenge in the treatment of GIST is resistance to tyrosine kinase inhibitor (TKI), which can be primary resistance, or more commonly due to the acquisition of secondary KIT/PDGFRA mutations or activation of alternative signalling pathways, such as the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway.[23]. Another mechanism of resistance to targeted therapies is due to insufficient levels of phosphatase and tensin homologue (PTEN) protein, which negatively regulates the PI3K/ AKT signalling pathway.[24]
The PI3K/AKT pathway plays an important role in the proliferation and survival of imatinibsensitive and -resistant GIST.[25]
Summary
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib. 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs. CONCLUSIONS: Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/ fourth-line advanced/metastatic GIST. Mutations in KIT exons 13 and 17 are rare.[4] A subset (5–8%) of GIST harbours PDGFRA mutations without the KIT mutations.[5,6] The first-line treatment for patients with primary
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