Background
GRID, phase III double-blind RCT. 199 patients with metastatic/unresectable GIST after failure of at least imatinib and sunitinib, randomized 2:1. Tested third-line therapy.
Interventions and follow up
Arm A: regorafenib 160mg daily, 3 weeks on / 1 week off (n=133)
Arm B: placebo (n=66); crossover to regorafenib permitted at progression
Primary endpoint: Progression-free survival (PFS)
Arm B: placebo (n=66); crossover to regorafenib permitted at progression
Primary endpoint: Progression-free survival (PFS)
Results
mPFS: 4.8mo vs 0.9mo, HR 0.27, 95%CI 0.19-0.39; P<.0001
OS: 29 (22%) vs 17 (26%) events, HR 0.77, 95%CI 0.42-1.41; P=.199 (no significant difference, confounded by crossover)
Best response: RR 4.5% vs 1.5%; SD 71.4% vs 33.0%
OS: 29 (22%) vs 17 (26%) events, HR 0.77, 95%CI 0.42-1.41; P=.199 (no significant difference, confounded by crossover)
Best response: RR 4.5% vs 1.5%; SD 71.4% vs 33.0%
Adverse events
Dermatologic: hand-foot skin reaction (grade 3-4 ~20%)
Cardiovascular: hypertension (grade 3-4 ~24%)
Other: diarrhea and fatigue common; dose modification frequently required
Cardiovascular: hypertension (grade 3-4 ~24%)
Other: diarrhea and fatigue common; dose modification frequently required
Conclusions
Regorafenib significantly improved PFS versus placebo in GIST that had progressed on imatinib and sunitinib, establishing it as standard third-line therapy.
Key Limitations
High crossover (85% of placebo patients) makes the OS comparison uninformative; objective responses were rare (benefit is mainly stable disease); substantial dermatologic and cardiovascular toxicity requires frequent dose interruption; mutation-specific efficacy not prospectively defined.
Clinical Context
FDA approved regorafenib for advanced GIST after imatinib and sunitinib in 2013. ESMO and ASCO position it as standard third-line therapy, with ripretinib as the standard fourth-line option (INVICTUS). A modified dose-escalation schedule is sometimes used to improve tolerability.