Ripretinib Yields Clinical Benefit Vs Sunitinib in Pretreated GIST Harboring KIT Exon Mutations

Ripretinib (Qinlock) appeared to improve clinical benefit compared with sunitinib (Sutent) in patients with gastrointestinal stromal tumors (GIST) harboring KIT exon 11 and 17 or 18 mutations previously treated with imatinib (Gleevec), according to a press release on an exploratory circulating tumor DNA (ctDNA) analysis from the phase 3 INTRIGUE trial (NCT03673501).

The median progression-free survival (PFS) was 14.2 months vs 1.5 months among patients in the ripretinib and sunitinib cohorts, respectively (HR, 0.22; 95% CI, 0.11-0.44; P <.0001). Additionally, the objective response rate (ORR) was 44.4% vs 0% in each respective arm (95% CI, 23.0%-62.7%; P = .0001). Trial investigators also reported an overall survival (OS) rate that was not estimable vs 17.5 months in each respective cohort (HR, 0.34; 95% CI, 0.15-0.76; P = .0061).

“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 or 18 mutations,” co-lead investigator Suzanne George, MD, associate division chief of the Sarcoma Center at Dana-Farber Cancer Institute, said in the press release.

Investigators of the randomized, global, multicenter phase 3 INTRIGUE study evaluated the efficacy and safety of ripretinib vs sunitinib in patients previously treated for GIST harboring KIT exon 11 and 17 or 18 mutations. A total of 453 patients were randomly assigned 1:1 to either receive 150 mg of ripretinib once a day or 50 mg of sunitinib once a day for 4 weeks followed by 2 weeks without sunitinib.

The primary end point of the INTRIGUE trial was PFS as evaluated by independent radiologic review per modified RECIST v1.1 criteria. Secondary end points included ORR and OS.

Patients 18 years and older with a histological diagnosis of GIST and an available archival tissue sample or fresh biopsy were eligible to enroll on the trial. Additional inclusion criteria included progression on imatinib, an ECOG performance status of 2 or less, at least 1 measurable lesion per modified RECIST v1.1 criteria, and adequate organ function and bone marrow reserve as indicated by central laboratory assessments.

Patients who received any additional lines of therapy following imatinib or had a prior or concurrent malignancy with the potential to interfere with safety or efficacy assessments were unable to enroll. Patients were also unsuitable for enrollment if they had active central nervous system metastases, a left ventricular ejection fraction less than 50% at screening, or any major surgery within 4 weeks of beginning study treatment.

Following results from the INTRIGUE study’s ctDNA analysis, plans have been made to launch the randomized, global, multicenter, open-label phase 3 INSIGHT study, which will compare the efficacy and safety of ripretinib and sunitinib in patients with GIST previously treated with imatinib harboring KIT exon 11 and 17/18 mutations. A total of 54 patients will be randomly assigned 2:1 to receive either ripretinib or sunitinib in the study.

“Given the strength of these results, and after consultation with the FDA, we plan to initiate our pivotal phase 3 INSIGHT study in the second half of 2023. If positive, we believe this trial will transform the standard of care for this subgroup of [patients with] second-line GIST based on their mutational profile,” Matthew Sherman, MD, chief medical officer at Deciphera, concluded.

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 6, 2023. bit.ly/3X7ZxNe