INTRIGUE study results show that patients with gastrointestinal stromal tumor who harbor certain KIT mutations have significantly improved responses and survival with ripretinib treatment.
Ripretinib (Qinlock) demonstrated clinical benefit in patients with gastrointestinal stromal tumor (GIST) who were previously treated with imatinib (Gleevec) and harbor mutations in KIT exon 11 and 17/18 only. This subgroup of patients with GIST is being treated in the phase 3 INTRIGUE study (NCT03673501).
“The newly reported clinical results from INTRIGUE demonstrate the remarkable differential benefit of ripretinib in patients with unique molecular subtypes of GIST in the second-line setting, specifically patients with ctDNA demonstrating KIT exon 11 and 17/18 mutations,” said Suzanne George, MD, associate division chief, Sarcoma Center, Dana-Farber Cancer Institute, and the co-lead investigator on the INSIGHT study, in a press release. “This data is potentially practice changing in second-line GIST and as ctDNA assays are increasingly optimized and utilized in the clinical arena, we must continue clinical drug development which aims to understand the impact of drugs in specific molecular subtypes of GIST with the goal to improve clinical outcomes by giving the right drug to the right patient at the right time.”
In the interventional, randomized, multicenter, open-label study, 453 patients with GIST make up the intent-to-treat population. Three hundred thirty-six patients had ctDNA testing to detect mutations, and KIT mutations were found in 213 patients at baseline. Of those with KIT mutations, the locations were exon 11 for 157 patients and exon 9 for 36 patients.
The common resistance mutations in KIT were in exon 17/18, impacting 89 patients as well as 13/14, which impacts 81 patients. Further, 52 of the patients with a KIT exon 11 primary mutations had a mutation in 17/18 only, while 41 patients had a mutation in 13/14 only, and 22 patients had mutations in both exon groups.
Objective responses to ripretinib were achieved in 44.4% of patients vs 0% of those treated with sunitinib (Sutent) in the control arm (95% CI, 23.0%-62.7%; P = .0001). Investigators found that patients with mutations in KIT exon 11 and exon 17/18 only had significant improvements in progression-free survival (PFS), objective response rate, and overall survival (OS) when treated with ripretinib vs sunitinib.
The median PFS was 14.2 months in the ripretinib arm compared with 1.5 months in the sunitinib arm (hazard ratio [HR], 0.22; 95% CI, 0.11-0.44; nominal P < .0001). The median OS was not estimable in the ripretinib arm compared with 17.5 months in the sunitinib arm (HR, 0.34; 0.15-0.76; nominal P = .0061).
“We are extremely pleased by the exploratory analysis showing that QINLOCK, already the standard of care for fourth-line GIST patients, provided substantial clinical benefit to this subgroup of second-line patients compared to sunitinib. We look forward to presenting additional data from the overall ctDNA analysis at a medical meeting later this month,” said Matthew L. Sherman, MD, chief medical officer of Deciphera, in the press release. “Given the strength of these results, and after consultation with the FDA, we plan to initiate our INSIGHT pivotal phase 3 study in the second half of 2023. If positive, we believe this trial will transform the standard of care for this subgroup of second-line GIST patients based on their mutational profile.”
In INSIGHT, roughly 54 patients with second-line GIST will be included and randomized 2:1 to receive ripretinib 150 mg daily or sunitinib 50 mg once daily for 4 weeks followed by 2 weeks without sunitinib. The key outcome of the study will be PFS as determined by independent radiologic review using modified RECIST 1.1 criteria. The study will begin in the second half of 2023.
1. Deciphera Pharmaceuticals announces results from ctDNA analysis from INTRIGUE phase 3 clinical study demonstrating substantial clinical benefit of QINLOCK® in second-line GIST patients with mutations in KIT Exon 11 and 17/18 only. News release. Deciphera Pharmaceuticals. January 3, 2023. Accessed January 5, 2023. https://bit.ly/3icztSr
2. A study of DCC-2618 vs sunitinib in advanced GIST patients after treatment with imatinib (intrigue). ClinicalTrials.gov. Updated January 6, 2021. Accessed January 5, 2022. https://clinicaltrials.gov/ct2/show/NCT03673501?term=ripretinib+INTRIGUE&draw=2&rank=1