KIT T670I

Background: The VOYAGER-trial compared avapritinib (ava) with regorafenib (rego) in patients (pts) with advanced gastrointestinal stromal tumors (GIST) in a 3rd-line setting. In a 3rd-line setting, pathogenic PIK3CA mutations represent the most common genomic event in an oncogenic KIT signaling intermediate but were found in only 4.7% of pts using ctDNA sequencing. The presence of PIK3CA mutations in plasma did not preclude prolonged disease control to ava or rego. Limitations of this analysis are the small sample size and the possibility of clonal hematopoiesis of indeterminate potential (CHIP) as PIK3CA mutations were not confirmed in tumor samples.

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.

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.

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.

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.

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).