Phase 3 Trial Shows Benefit of Ripretinib in Second-Line Gastrointestinal Stromal Tumor Treatment

Results from the phase 3 INTRIGUE clinical trial have found substantial clinical benefit of ripretinib (Qinlock, Deciphera Pharmaceuticals) in the second-line treatment of gastrointestinal stromal tumor (GIST) in patients previously treated with imatinib who harbor mutations in KIT exon 11 and 17/18 only.

The planned INSIGHT phase 3 trial is a randomized, global, multicenter, open-label study evaluating the efficacy and safety of ripretinib compared to sunitinib. In the study, 54 patients were randomized 2:1 to either ripretinib 150 mg once daily or sunitinib 50 mg once daily for 4 weeks followed by 2 weeks without sunitinib. The primary endpoint is progression-free survival (PFS) and secondary endpoints include objective response rate (ORR) and overall survival (OS).

“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 co-lead investigator Suzanne George, MD, 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.”

The new findings come from a planned exploratory efficacy analysis using circulating tumor DNA (ctDNA) to explore the efficacy of ripretinib according to baseline KIT primary and secondary mutation status. Of the 453 patients in the overall intent-to-treat (ITT) study population, baseline ctDNA was analyzed in 362 patients for whom evaluable samples were available. ctDNA was detected in 280 samples and KIT mutations were detected in 213 patients.

Baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing liquid biopsy assay. Primary mutations in KIT were detected in exon 11 in 157 patients and in exon 9 in 36 patients.

Common resistance mutations in KIT were detected in exons 17/18 in 89 patients and in exons 13/14 in 81 patients. In patients with a KIT exon 11 primary mutation, 52 patients had mutations in exon 17/18 only, 41 had mutations in exon 13/14 only, and 22 patients had mutations in both exon 13/14 and exon 17/18.

According to the study results, patients with mutations in KIT exon 11 and exon 17/18 only had substantially improved PFS, ORR, and OS with ripretinib versus sunitinib. Efficacy results in patients with detectable ctDNA in KIT exon 11 and in the ITT populations were consistent with the primary analysis of the INTRIGUE study based on tumor data used for randomization. Subgroup safety profiles were consistent with the primary analysis.

The analysis found a median PFS of 14.2 months in the ripretinib arm compared with 1.5 months in the sunitinib arm. Similarly, researchers found an ORR of 44.4% in the ripretinib arm versus 0% in the sunitinib arm.

The OS was not estimable in the ripretinib arm and was 17.5 months in the sunitinib arm.

“We are extremely pleased by the exploratory analysis showing that Qinlock, already the standard of care for fourth-line GIST patients, providing 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.”

REFERENCE

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 11, 2023. https://investors.deciphera.com/news-releases/news-release-details/deciphera-pharmaceuticals-announces-results-ctdna-analysis