Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial

Abstract

Ripretinib; Gastrointestinal stromal tumor; Biomarker

Ripretinib; Tumor del estroma gastrointestinal; Biomarcador

Ripretinib; Tumor de l'estroma gastrointestinal; Biomarcador

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.

The INTRIGUE study was funded by Deciphera Pharmaceuticals, and as the sponsor, Deciphera contributed to the conception, design and analysis of the study. We thank the patients and their families and caregivers, the investigators and the investigational site staff of the INTRIGUE study. We also thank M. Kusi for her contributions to this manuscript and Guardant Health for processing plasma samples and providing the relevant methods. M.C.H. received partial salary support from the following sources: a research grant from the Jonathan David Foundation, a VA Merit Review Grant (I01BX005358) and NCI R21 grant (R21CA263400). Medical writing support was provided by L. Hanlon and M. Chakhtoura of AlphaBioCom, a Red Nucleus company, and was funded by Deciphera Pharmaceuticals, in compliance with international good publication practice guidelines.