Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial

Abstract

Purpose: Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib is a switch-control TKI approved for advanced GIST after prior treatment with three or more TKIs, including imatinib. We compared efficacy and safety of ripretinib versus sunitinib in patients with advanced GIST who were previously treated with imatinib (INTRIGUE, ClinicalTrials.gov identifier: NCT03673501).

Patients and methods: Random assignment was 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off) and stratified by KIT/platelet-derived growth factor α mutation and imatinib intolerance. The primary end point was progression-free survival (PFS) by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included objective response rate by independent radiologic review, safety, and patient-reported outcome measures.

Results: Overall, 453 patients were randomly assigned to ripretinib (intention-to-treat [ITT], n = 226; KIT exon 11 ITT, n = 163) or sunitinib (ITT, n = 227; KIT exon 11 ITT, n = 164). Median PFS for ripretinib and sunitinib (KIT exon 11 ITT) was 8.3 and 7.0 months, respectively (hazard ratio, 0.88; 95% CI, 0.66 to 1.16; P = .36); median PFS (ITT) was 8.0 and 8.3 months, respectively (hazard ratio, 1.05; 95% CI, 0.82 to 1.33; nominal P = .72). Neither was statistically significant. Objective response rate was higher for ripretinib versus sunitinib in the KIT exon 11 ITT population (23.9% v 14.6%, nominal P = .03). Ripretinib was associated with a more favorable safety profile, fewer grade 3/4 treatment-emergent adverse events (41.3% v 65.6%, nominal P < .0001), and better scores on patient-reported outcome measures of tolerability.

Conclusion: Ripretinib was not superior to sunitinib in terms of PFS. However, meaningful clinical activity, fewer grade 3/4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.

FIG 1.

CONSORT diagram for the phase III INTRIGUE study. IRR, independent radiologic review; ITT, intention-to-treat; PD, progressive disease.

FIG 2.

Kaplan-Meier analysis of PFS for patients treated with ripretinib or sunitinib in the (A) KIT exon 11 ITT population and (B) the ITT population; (C) forest plot of PFS by stratification factors for patients treated with ripretinib or sunitinib. HRs were obtained from stratified Cox regression model and P values were from two-sided stratified log-rank tests. HR, hazard ratio; ITT, intention-to-treat; PDGFRA, platelet-derived growth factor receptor alpha; PFS, progression-free survival; WT, wild-type.

FIG 3.

Butterfly plots of TEAEs (≥ 10% in either arm) of (A) all grades and (B) grade 3/4 TEAEs (≥ 2% in either arm). AEs were labeled and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0; AEs were considered treatment emergent if they occurred after administration of the first dose of study drug through 30 days after the last dose of study drug. AE, adverse event; TEAE, treatment-emergent AE.