INSIGHT: A phase 3, randomized, open-label study of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib with
KIT
exon 11 + 17/18 mutations.
Authors: Heinrich Michael C. , Blay Jean-Yves , Chi Ping , Jones Robin Lewis , Serrano César , Somaiah Neeta , Gelderblom Hans , Zalcberg John Raymond , Reichmann William , Sprott Kam , Sherman Matthew L. , Bauer Sebastian , George Suzanne ,   on behalf of the INSIGHT study investigators
Published: January 2025

TPS848

Background:
Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by
KIT
mutations. Most patients (pts) with advanced GIST experience disease progression following first-line treatment with imatinib due to
KIT
secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the INTRIGUE phase 3 study (NCT03673501) in second-line therapy for advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib (Bauer S et al.
J Clin Oncol
. 2022). Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary
KIT
exon 11 mutations with secondary resistance mutations exclusively in
KIT
exons 17/18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR, 0.22; 95% CI, 0.11 to 0.44; nominal
P
<0.0001; Heinrich MC et al.
Nat Med
. 2024). Here, we describe an ongoing phase 3 study for pts with advanced GIST previously treated with imatinib harboring
KIT
exon 11 + 17/18 mutations.
Methods:
INSIGHT (NCT05734105) is a phase 3, randomized, open-label study designed to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor
KIT
exon 11 + 17/18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring
KIT
exon 11 + 17/18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include a
KIT
exon 9, 13, or 14 mutation confirmed via ctDNA analysis at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. This abstract was originally presented at ASCO 2023.
Clinical trial information: NCT05734105
.