ctDNA Reveals KIT Mutation-Dependent Drug Sensitivity in GIST: INTRIGUE Trial Biomarker Analysis
Exploratory ctDNA analysis from the phase 3 INTRIGUE trial in advanced gastrointestinal stromal tumors identified two mutually exclusive KIT mutation populations with dramatically different drug sensitivities: patients with KIT exon 11+17/18 mutations had median PFS of 14.2 months on ripretinib versus 1.5 months on sunitinib, while those with exon 11+13/14 mutations responded better to sunitinib. The findings demonstrate that ctDNA-based mutational profiling can predict differential efficacy of targeted therapies and guide rational drug selection in GIST.
The original study
Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.
- Authors
- Heinrich MC, Jones RL, George S, Gelderblom H, Schöffski P, von Mehren M, et al.
- Journal
- Nature medicine
- Type
- Randomized Controlled Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
- PMID
- 38182785
Original abstract
INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.