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REVISITING IN- AND OFF LABEL DRUGS FREQUENTLY USED IN METASTATIC GIST USING A BROAD IN VITRO PROFILING PANEL OF PRIMARY AND SECONDARY KIT AND PDGFRA-MUTANT GIST CELLS – CLINICAL IMPLICATIONS (CTOS 2023)
Apart from approved drugs (imatinib, sunitinib, regorafenib, ripretinib, and avapritinib, we evaluated cabozantinib, pazopanib, dasatinib, and sorafenib... Preclinical testing suggests that dose-escalation of or retreatment with imatinib is not effective in exon 11 mutant GIST with secondary mutations. Pazopanib appears highly ineffective against any secondary mutation but shows notable activity in exon 9 mutant GIST. Cabozantinib is the only drug with strong activity against the gatekeeper T670I and the AL D820Y mutation.
Preclinical • Metastases
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • PDGFRA D842V • PDGFRA mutation • KIT T670I
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dasatinib • sorafenib • imatinib • Sutent (sunitinib) • Votrient (pazopanib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • Ayvakit (avapritinib) • Qinlock (ripretinib)
over1year
NILOTINIB REVISITED: SALVAGE USE IN PATIENTS WITH SEVERE IMATINIB-TOXICITY (CTOS 2022)
Despite the small-sized cohort, our data suggests that for patients with severe imatinib-toxicity, nilotinib may represent a well-tolerated alternative – particularly in the context of its imminent patent expiration. We show for the first time a secondary mutation in exon 9 as mechanism of resistance to a highly specific KIT inhibitor that lacks activity against primary exon 9 mutations. Additional analyses are currently being performed to gain insight into the properties of nilotinib and imatinib to support the observations from clinical and in vitro settings.
Clinical
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • PDGFRA mutation • KIT T670I
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imatinib • Tasigna (nilotinib)
almost2years
Circulating tumor DNA (ctDNA) analyses of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor (GIST). (ASCO 2022)
Background: The genotype of primary mutations predicts imatinib response in untreated metastatic GIST...Regorafenib showed similar activity regardless of KIT mutational status and the location of KIT mutation... Hybrid capture-based plasma sequencing detects ctDNA in the majority of patients with advanced TKI-resistant GIST, including heterogeneity of KIT mutations. This study is the first to show that ctDNA sequencing correlates with outcomes in pretreated GIST. Identification of ABP (exon13/14) KIT mutations negatively correlates with avapritinib activity.
P3 data • Clinical • Circulating tumor DNA
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • KIT positive • PDGFRA mutation • KIT exon 17 mutation • KIT T670I • KIT V654A
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Guardant360® CDx
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imatinib • Stivarga (regorafenib) • Ayvakit (avapritinib)
almost2years
Nintedanib overcomes drug resistance from upregulation of FGFR signaling and imatinib-induced KIT mutations in gastrointestinal stromal tumors. (PubMed, Mol Oncol)
In vivo antitumor activity was also observed in several xenograft GIST models. Considering the well-documented safety and pharmacokinetic (PK) profiles of nintedanib, this finding provides evidence for the repurposing of nintedanib as a new therapy for the treatment of GIST patients with de novo or acquired resistance to imatinib.
Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • FGFR (Fibroblast Growth Factor Receptor)
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KIT mutation • KIT T670I
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imatinib • nintedanib
over3years
Design of antitumor drugs targeting c-kit receptor by a new mixed ligand-structure based method. (PubMed, J Mol Graph Model)
The comparison between the explored ligands and well-known drugs highlights the possibility to overcome tumor-acquired resistance. The best-selected structures (630705 and SML1348) provide valuable binding affinities with the mutated c-Kit forms (respectively T670I and V654A).
Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT T670I • KIT D816H