INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib

Abstract

359881 Background: Sunitinib is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI), is indicated for the treatment of adult patients (pts) with GIST who received prior treatment with 3 or more TKIs, including imatinib. We compared the efficacy and safety of ripretinib vs sunitinib in pts with advanced GIST who progressed on or were intolerant to imatinib. Methods: This multicenter, global, randomized, open-label phase 3 study (NCT03673501) enrolled adult pts 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 wks on/2 wks off). Randomization was stratified by KIT mutational status and imatinib intolerance. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using modified RECIST version 1.1. Key secondary endpoints were objective response rate (ORR) by IRR and overall survival (OS). Hierarchical testing was performed for primary and key secondary endpoints in a prespecified sequence; testing pts with a KIT exon 11 primary mutation (Ex11 intention-to-treat [ITT] population) preceded the all-patient (AP) ITT population. Data cutoff was 1 Sep 2021; final analyses of PFS and ORR and the first interim analysis of OS were conducted. Results: A total of 453 pts were randomized to ripretinib (n = 226; Ex11 ITT, n = 163) or sunitinib (n = 227; Ex11 ITT, n = 164). Median age was 60 yrs (range 18–88) and most pts were white (66.2%) males (62.0%). PFS was not statistically different between ripretinib and sunitinib in the Ex11 ITT (hazard ratio [HR] 0.88, 95% CI 0.66, 1.16; P = 0.36; median 8.3 vs 7.0 mos) or in the AP populations (HR 1.05, 95% CI 0.82, 1.33; P = 0.72; median 8.0 vs 8.3 mos). ORR was numerically higher for ripretinib vs sunitinib in the Ex11 ITT (23.9% vs 14.6%; difference 9.3%, 95% CI 0.7, 17.8; nominal P = 0.03) and AP ITT populations (21.7% vs 17.6%; difference 4.2%, 95% CI −3.2, 11.5; nominal P = 0.27). OS data was highly immature; median OS was not reached in either arm. Fewer pts in the ripretinib arm experienced Grade 3-4 (G3-4) treatment-emergent adverse events (TEAEs) vs sunitinib (41.3% vs 65.6%). Among G3-4 TEAEs with a difference ≥5% between arms, ripretinib had fewer events vs sunitinib (hypertension [8.5% vs 26.7%], palmar-plantar erythrodysesthesia [1.3% vs 10.0%], neutropenia [0% vs 6.3%], and neutrophil count decreased [0% vs 7.2%]). Conclusions: The PFS in both arms was longer than PFS achieved by sunitinib in its pivotal phase 3 trial. While the PFS for ripretinib did not meet the primary endpoint of superiority vs sunitinib, meaningful clinical activity and fewer G3-4 TEAEs were observed in pts with advanced GIST treated with ripretinib after imatinib failure. Clinical trial information: NCT03673501.

Systemic Therapy for Gastrointestinal Stromal Tumor: Current Standards and Emerging Challenges

“…The phase III trial (INVICTUS) confirmed the role of ripretinib as the fourth-line treatment based on a median PFS of over 6 months compared to only 1 month in the placebo arm. The preliminary results of the phase III INTRIGUE trial showed that ripretinib is not superior to sunitinib as a second-line TKI for patients with GIST in terms of progression-free survival [ 26 ]. The relative safety profile similar to imatinib provides heavily pretreated patients a feasible drug of choice.…”

An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors

“…A total of 453 patients with GIST were enrolled in this study, where 226 patients received continuous dosing of 150 mg of ripretinib and 227 patients received continuous dosing of 50 mg of sunitinib (4-week on and 2-week off). Although the study did not meet its primary endpoint, progression-free survival (PFS) in ripretinib treated patients was not superior those treated with sunitinib, but there were significant advantages in ORR and safety profiles ( 42 ). In all population, mPFS was similar in patients treated with ripretinib compared to those treated with sunitinib: 8.0 months vs 8.3 months (HR = 1.05, 95% CI 0.82 to 1.33).…”

“…In the INTRIGUE STUDY, the safety profile of ripretinib was improved compared to that of sunitinib, with a lower incidence of grade 3/4 AEs (26.5% vs 55.2%). For grade 3/4 AEs with an incidence of ≥2%, the incidence of these events was also lower in the ripretinib group than in the sunitinib group ( 42 ).…”

Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients

“…Ripretinib has also been assessed compared to sunitinib in the phase III INTRIGUE study in patients with advanced GIST after treatment with imatinib. PFS was not statistically different between the ripretinib and sunitinib arms, and median OS was not reached in either arm [ 55 ].…”