(P 46) CIRCULATING TUMOR DNA (CTDNA) ANALYSES AND RESISTANCE MECHANISMS EXPLORATION OF KIT-MUTANT GASTROINTESTINAL STROMAL TUMORS (GISTS) TREATED WITH AVAPRITINIB OR RIPRETINB

Objective: Resistance mechanisms of avapritinib and ripretinib, two novel TKIs for GISTs, have not been fully elucidated. CtDNA NGS-based sequencing is valuable for describing the complex landscape of resistant GISTs, overcoming the problem of heterogeneity. Here, we characterized the genomic heterogeneity of plasma samples from patients with advanced GISTs at baseline and progression of avapritinib or ripretinib to understand the mechanisms of resistance.

Methods: Liquid biopsies (plasma ctDNA) of patients with advanced GISTs in Peking University Cancer Hospital & Institute, were collected predose on Cycle 1 Day 1 and after failure of avapritinib or ripretinib and were profiled using an NGS liquid biopsy assay.

Results: CtDNA analysis at baseline and progression was performed in 25 patients treated with avapritinib. CtDNA was detected in 80% samples, with KIT mutations detected in 60%. A total of 37 KIT mutations were detected in progression samples of 17 patients (mean, 2.18). KIT exon 17 missense mutations (9/37, 35.1%), KIT exon 9 duplication mutations (6/37, 16.2%) and KIT exon 11 deletion mutations (5/37, 13.5%) were commonly detected. KIT exon 9 duplication mutation rate was significantly increased in progression samples compared with baseline. Meanwhile, novel mutation types that were not present at baseline, such as KIT exon13/14/16 missense mutations, exon13 insertion mutations and exon 8 deletion mutations, were detected in progression samples. In addition to KIT mutations, other common signaling pathway alterations at progression of avapritinib were detected, mainly located in PI3K-Akt pathway and cell cycle pathway, followed by RTK-RAS pathway. Plasma ctDNA was analyzed in 25 patients at baseline and 14 patients after failure of ripretinib. CtDNA was detected in 66.7% samples, with KIT mutations detected in 61.5%. A total of 16 KIT mutations were detected in progression samples of 9 patients (mean, 1.78). KIT exon 11 deletion mutations (3/16), deletion insertion mutations (3/16) and missense mutations (3/16) were commonly detected. Exon 11 missense mutations, followed by KIT exon 14 missense mutations and KIT exon11 deletion insertion mutations were significantly increased in progression samples compared with baseline. The most common signaling pathways activation at progression of ripretinib included TP53-related pathway, RTK-RAS pathway, Cell-cycle pathway, MYC pathway and NOTCH pathway.

Conclusion: Different KIT mutation types and signaling pathways atlerations were detected in progression samples of KIT-mutant GISTs after avapritinib or ripretinib failure compared with baseline, which may be associated with mechanism of resistance.