Background
INVICTUS, phase III double-blind RCT. 129 patients with advanced GIST previously treated with at least imatinib, sunitinib and regorafenib, randomized 2:1. Tested fourth-line therapy with ripretinib, a switch-control KIT/PDGFRA inhibitor.
Interventions and follow up
Arm A: ripretinib 150mg daily until progression (n=85)
Arm B: placebo (n=44); crossover to ripretinib permitted at progression
Primary endpoint: Progression-free survival (PFS)
mFollow up: 6.3mo
Arm B: placebo (n=44); crossover to ripretinib permitted at progression
Primary endpoint: Progression-free survival (PFS)
mFollow up: 6.3mo
Results
mPFS: 6.3mo vs 1.0mo, HR 0.15, 95%CI 0.09-0.25; P<.0001
mOS: 15.1mo vs 6.6mo, HR 0.36, 95%CI 0.21-0.62
12-mo OS: 65.4% vs 25.9%
ORR: 9% vs 0%
mOS: 15.1mo vs 6.6mo, HR 0.36, 95%CI 0.21-0.62
12-mo OS: 65.4% vs 25.9%
ORR: 9% vs 0%
Adverse events
Common treatment-related (≥20%): alopecia, myalgia, nausea, fatigue, palmar-plantar erythrodysesthesia, diarrhea
Grade 3-4 treatment-related: lipase increase 5%, hypertension 4%, fatigue 2%, hypophosphatemia 2%
Overall: grade 3-4 events 49% (ripretinib) vs 44% (placebo); discontinuation for AEs ~8%
Grade 3-4 treatment-related: lipase increase 5%, hypertension 4%, fatigue 2%, hypophosphatemia 2%
Overall: grade 3-4 events 49% (ripretinib) vs 44% (placebo); discontinuation for AEs ~8%
Conclusions
Ripretinib significantly improved PFS and OS versus placebo in GIST that had progressed on at least three prior TKIs, with a manageable safety profile.
Key Limitations
Small fourth-line population with short median follow-up; placebo crossover and small numbers limit precision of OS; low objective response rate (benefit largely disease stabilization). In second-line (INTRIGUE), ripretinib did not outperform sunitinib, so its established role remains the ≥4th-line setting.
Clinical Context
FDA approved ripretinib (May 2020) for advanced GIST after at least three prior TKIs (imatinib, sunitinib, regorafenib). ESMO and ASCO recommend ripretinib as standard fourth-line therapy. It is not recommended in the second-line setting after the negative INTRIGUE trial versus sunitinib.