Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE.

Background: Ripretinib, a switch-control tyrosine kinase inhibitor (TKI), is indicated for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with >= 3 TKIs, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. Circulating tumor DNA (ctDNA) analysis may provide insight into the efficacy of these agents in second-line advanced GIST. Here, we present exploratory baseline ctDNA results from INTRIGUE. Methods: INTRIGUE is an open-label, phase 3 study that enrolled adult pts with advanced GIST who progressed on or had intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are reported here. Results: Of 453 pts in the overall intent-to-treat (ITT) population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%), with KIT mutations detected in 213/280 (76%). Common resistance mutations were in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in pts with detectable ctDNA in the KIT exon 11 and overall ITT populations was consistent with the primary analysis based on tumor data used for randomization. Pts with KIT exon 11 + 17/18 (-9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with ripretinib vs sunitinib, whereas pts with exon 11 + 13/14 (-9/17/18) mutations had better PFS, ORR, and OS with sunitinib vs ripretinib (Table). Subgroup safety profiles were consistent with the primary analysis. Conclusions: While KIT ATP-BP mutations predicted clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of the complex landscape of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in pts with advanced GIST. Clinical trial information: NCT03673501. Outcomes by ctDNA analysis.AL (KIT exon 11 + 17/18)(-9/13/14)R vs SATP-BP (KIT exon 11 + 13/14)(-9/17/18)R vs SAL/ATP-BP co-mutants (KIT exon 11 +13/14 + 17/18)(-9)R vs S Pts, n27 vs 2521 vs 2011 vs 11mPFSa, monthsHR (CI)14.2 vs 1.50.22 (0.11, 0.44)4.0 vs 15.03.94 (1.71, 9.11)8.1 vs 10.91.07 (0.41, 2.84)ORRa, %RD, % (CI)44.4 vs 044.4 (23.0, 62.7)9.5 vs 15.0-5.5 (-27.6, 16.2)27.3 vs 9.118.2 (-15.4, 48.4)mOSb, monthsHR (CI)NE vs 17.50.34 (0.15, 0.76)24.5 vs NE1.75 (0.72, 4.24)14.7 vs 20.32.61 (0.95, 7.19)Data cut: aSept 1, 2021; bSept 1, 2022. CI, 95% confidence interval; HR, hazard ratio; m, median; NE, not estimable; R, ripretinib; RD, response difference; S, sunitinib.