INVICTUS: A phase III, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as ≥ 4th-line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753)

Abstract

Background Ripretinib is a switch-control kinase inhibitor that broadly inhibits KIT- and PDGFRA-mutated kinases by regulating the kinase switch pocket and activation loop. Methods Patients (pts) with advanced GIST who received prior treatment with at least imatinib, sunitinib, and regorafenib were enrolled. Pts were randomized 2:1 to ripretinib 150 mg QD or placebo (P) and stratified by 3 v ≥ 4 prior therapies and ECOG 0 v 1-2. Patients with a PD on 150 mg QD were allowed to dose escalate and patients on P arm crossed over to ripretinib at PD. The primary end point was PFS per blinded independent central review. Secondary end points included objective response rate (ORR; key end point) and OS. Results 129 pts were randomized as ITT. In the double-blind period, ripretinib improved median PFS over P (6.3 v 1 mo; HR = 0.15; 95%CI: 0.09,0.25; P < 0.0001). PFS rates at 6 mo were 51% (95%CI: 39.4,61.4) for ripretinib and 3.2% (95%CI: 0.2,13.8) for P. Analysis of PFS in pt subgroups assessed favored ripretinib. ORR was 9.4% for ripretinib and 0% for P (P = 0.0504; median duration not reached). Ripretinib demonstrated an improvement over P in median OS (15.1 v 6.6 mo; HR = 0.36; 95%CI: 0.20,0.62; nominal P = 0.0004). OS rates at 12 mo were 65.4% (95%CI: 51.6,76.1) for ripretinib and 25.9% (95%CI: 7.2,49.9) for P. Ripretinib was generally well tolerated. Any dose reductions were in 7 pts (8.2%) in ripretinib arm v 1 (2.3%) in P arm; interruptions were in 18 pts (21.2%) in ripretinib v 8 (18.6%) in P arm. Conclusions Ripretinib improved PFS over P in advanced GIST patients after progression on standard treatments. Ripretinib was associated with a favorable tolerability profile. Ripretinib is a novel therapy in a population with no other approved therapy and may represent a new standard of care. Clinical trial identification NCT03353753. Editorial acknowledgement Medical writing assistance was provided by Laura Jung, PharmD, of ETHOS Health Communications in Yardley, Pennsylvania, and financially supported by Deciphera Pharmaceuticals, Inc. Legal entity responsible for the study Deciphera Pharmaceuticals, LLC. Funding Deciphera Pharmaceuticals, LLC.