Nature Medicine publication of results from exploratory ctDNA analysis from INTRIGUE phase III study demonstrates substantial clinical benefit of Qinlock (ripretinib) in 2L GIST patients with mutations in KIT Exon 11 and 17/18.- Deciphera Pharmaceuticals

The article, titled “Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase III INTRIGUE trial” is now available online and will be published in a future print issue of Nature Medicine.

“The results published in Nature Medicine provide compelling evidence that Qinlock may provide progression-free and overall survival benefit to second-line (2L) GIST patients in whom a liquid biopsy reveals primary KIT exon 11 mutations plus secondary mutations restricted to KIT exons 17 and 18. It is the first test that measures heterogeneity of resistance and may allow for a more optimized and targeted treatment plan for people living with this disease,” said Sebastian Bauer, M.D., Medical Oncologist at the West German Cancer Center in Essen and senior author of the manuscript. “This analysis is leading us to consider a new approach in GIST treatment using sensitive and minimally invasive blood tests to identify the specific secondary mutational profile for individual patients in order to tailor their therapy based on the differential activity of Qinlock and sunitinib seen in the INTRIGUE subgroup analysis.”

“In second-line GIST patients with KIT exon 11 + 17/18 mutations only, treatment with Qinlock resulted in a 78% reduction in the risk of disease progression and a 66% reduction in the risk of death compared to sunitinib, representing a substantial clinical benefit for these patients,” said Matthew L. Sherman, M.D., Chief Medical Officer of Deciphera. “Our ongoing INSIGHT pivotal Phase III study is designed to confirm the exceptional efficacy we observed in this exploratory analysis from INTRIGUE. The INSIGHT study is now open at multiple sites and we are committed to enrolling the study as quickly as possible.”

INTRIGUE is an international, multi-center study conducted in 122 active sites across 22 countries, where 453 patients in the all patient intent-to-treat population (AP-ITT) with second-line GIST were randomized to receive ripretinib (n=226) or sunitinib (n=227). In the AP-ITT population, Qinlock demonstrated similar efficacy with a median progression-free survival (PFS) of 8.0 months versus 8.3 months for sunitinib (HR 1.05, nominal p=0.72). There were fewer patients with Grade 3-4 drug-related treatment emergent adverse events (TEAE) with Qinlock (26.5%) compared with sunitinib (55.2%). Based on the primary results from the INTRIGUE study, Qinlock was included in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (version 1.2023) as the preferred second-line regimen for patients with advanced GIST who are intolerant to sunitinib.

A prespecified exploratory objective in INTRIGUE was to evaluate anti-tumor efficacy of Qinlock according to baseline KIT primary and secondary mutation status. Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing liquid biopsy assay in patients for whom evaluable samples were available (n=362) out of whom 280 patients had detectable ctDNA. In patients with a detectable KIT exon 11 primary mutation (n=157), 52 patients also had mutations in KIT exon 17/18 only and 41 had mutations in KIT exon 13/14 only.

Patients with mutations in KIT exon 11 and 17/18 only had improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with Qinlock versus sunitinib while patients with mutations in KIT exon 11 and 13/14 only had improved PFS, ORR, and OS with sunitinib compared to Qinlock.

The subgroup safety profile was consistent with the primary analysis in the AP-ITT population and demonstrated a more favorable safety profile for Qinlock compared with sunitinib with fewer patients experiencing Grade 3-4 drug-related TEAEs (KIT exon 11 and 17/18 only: 33.3% for Qinlock versus 50.0% for sunitinib).

See- Heinrich, M.C., Jones, R.L., George, S. et al." Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial." Nat Med (2024). https://doi.org/10.1038/s41591-023-02734-5.