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.

A systematic review and network meta-analysis of the efficacy and safety of third-line and over third-line therapy after imatinib and TKI resistance in advanced gastrointestinal stromal tumor

“…Ripretinib is approved for the treatment of adult patients with advanced GIST who have received prior treatment with ≥3 TKIs including imatinib ( Lostes-Bardaji et al, 2021 ). Recently, a phase III study of ripretinib versus sunitinib for the treatment of advanced GISTs after the failure of imatinib (INTRIGUE) was completed ( Bauer et al, 2022 ). However, ripretinib did not meet the primary end point of superiority in the PFS over sunitinib (8 months vs. 8.3 months), whereas ORR was higher for patients receiving ripretinib in the KIT exon 11 population and ripretinib has a more favorable safety profile ( Bauer et al, 2022 ).…”

“…Recently, a phase III study of ripretinib versus sunitinib for the treatment of advanced GISTs after the failure of imatinib (INTRIGUE) was completed ( Bauer et al, 2022 ). However, ripretinib did not meet the primary end point of superiority in the PFS over sunitinib (8 months vs. 8.3 months), whereas ORR was higher for patients receiving ripretinib in the KIT exon 11 population and ripretinib has a more favorable safety profile ( Bauer et al, 2022 ). Although ripretinib did not seem to defeat sunitinib regarding second-line therapy for GISTs, it still performed better in this network meta-analysis, which suggests ripretinib as a high priority in fourth-line therapy.…”

“…Avapritinib has excellent efficacy in the treatment of unresectable or metastatic PDGFRA D842V mutant GISTs ( Heinrich et al, 2020 ). Ripretinib, as a broad-spectrum KIT and PDGFRA switch-control TKI, showed excellent efficacy against various primary and secondary mutation types in the fourth-line treatment of GIST, although it can be observed from the genotyping data of the INTRIGUE study that efficacy against different genetic subtypes is still different ( Blay et al, 2020 ; Bauer et al, 2022 ). Precise targeted therapy is a very important direction for the future treatment of GIST, and more high-quality studies of new agents are expected.…”

“…As the assessment of OS required a long period of time, Mir et al (2016) and Kang et al (2021) did not report the HR of OS because it was not reached. In terms of AEs, the total number of grade 3–5 AEs were not present in studies by Mir et al (2016 ) and Blay et al (2020 ), and we could not calculate it by the accumulation either because patients might suffer from more than one pattern of AE; therefore, pazopanib and ripretinib were not included in the comparison even though ripretinib was reported to have a more favorable safety profile compared with sunitinib ( Bauer et al, 2022 ).…”

The Role of Regorafenib in the Management of Advanced Gastrointestinal Stromal Tumors: A Systematic Review

“…Imatinib-resistant patients can be treated with the second-line multi-kinase inhibitor sunitinib malate (SM) with a recommended dose of 50mg once daily in six-week cycles with four weeks on medication and two weeks off until progression of the disease or unmanageable toxicity [ 12 ]. INTRIGUE study reported similar benefits of ripretinib as a second-line therapy, compared to sunitinib, with a more tolerable safety profile and patient-reported outcomes (PRO) [ 13 ].…”