Efficacy and safety of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: A phase 2 multicenter, randomized, open-label study in China.
Authors: Li Jian , Zhang Jun , Zhang Yanqiao , Qiu Haibo , Zhou Yanbing , Zhou Yongjian , Zhang Xinhua , Zhou Ye , Zhu Yuping , Li Yong , Wang Ming , Shen Kuntang , Tao Kaixiong , Wu Xin , Wang Haijiang , Zhang Bo , Ling Jiayu , Ye Yingjiang , Dong Juan , Shen Lin 
Published: January 2023

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Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for the fourth-line therapy for GIST. In the INTRIGUE study (NCT03673501), ripretinib as second-line (2L) treatment demonstrated similar progression-free survival (PFS) and fewer Grade 3/4 treatment-emergent adverse events (TEAEs) compared to sunitinib in the overall population. It showed a numerically longer PFS and a nominally higher objective response rate (ORR) than sunitinib in patients (pts) with KIT exon 11 mutations. This study aims to evaluate the efficacy and safety of ripretinib vs sunitinib as 2L treatment in GIST pts in China. Methods: This multicenter, randomized, open-label phase 2 study (NCT04633122) enrolled adults with GIST who progressed on or had intolerance to imatinib. Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 42-day cycles. Randomization was stratified by KIT mutational status. The primary endpoint was PFS by independent radiologic review (IRR) using modified RECIST version 1.1. Secondary endpoints included ORR by IRR, overall survival (OS) and safety. Efficacy analysis was performed in all-patients intent-to-treat (AP ITT) and KIT exon 11 mutation intent-to-treat (Ex11 ITT) populations. This study was designed to bridge the global trial (INTRIGUE) to show consistency in the efficacy of ripretinib between the two studies. No statistical testing was pre-specified and nominal p-values were presented for descriptive purpose. Results: Overall, 108 pts were randomized to ripretinib (AP ITT n= 54; Ex11 ITT n=35) or sunitinib (AP ITT n= 54; Ex11 ITT n=35). Median age was 59.0 years (range 25–82); 63.9% of pts were male and 57.4% had ECOG PS≥1. By primary data cut-off (20 Jul 2022), PFS by IRR was similar between ripretinib and sunitinib in AP ITT population (HR 0.99, 95% CI 0.57, 1.69; p=0.92; median PFS [mPFS] 10.3 vs 8.3 months). ORR by IRR was numerically higher for ripretinib than sunitinib (29.6% vs 20.4%). Median OS was not reached in either arm. In Ex11 ITT population, a longer PFS by IRR (HR 0.46, 95% CI 0.23, 0.92; p=0.03; mPFS not reached for ripretinib and 4.9 months for sunitinib) and a numerically higher ORR by IRR (37.1% vs 22.9%) were observed for ripretinib vs sunitinib. Fewer Grade 3/4 treatment-related TEAEs were reported with ripretinib than with sunitinib (16.7% vs 55.6%), as were treatment-related TEAEs leading to dose interruption (7.4% vs 42.6%), dose reduction (20.4% vs 29.6%) and treatment discontinuation (1.9% vs 7.4%). Conclusions: Similar to the INTRIGUE trial, ripretinib demonstrated comparable overall efficacy and favorable safety vs sunitinib as 2L therapy in Chinese pts with advanced GIST. 2L GIST pts harboring a KIT exon 11 mutation may benefit from ripretinib vs sunitinib. Clinical trial information: NCT04633122 .