Background
Phase III RCT (SWOG S0033/CALGB intergroup). 746 patients with advanced or metastatic c-KIT-positive GIST. Tested standard- vs high-dose first-line imatinib.
Interventions and follow up
Arm A: imatinib 400mg daily
Arm B: imatinib 400mg twice daily (800mg/day)
Primary endpoint: Progression-free survival (PFS) and overall survival (OS)
mFollow up: 4.5yr
Arm B: imatinib 400mg twice daily (800mg/day)
Primary endpoint: Progression-free survival (PFS) and overall survival (OS)
mFollow up: 4.5yr
Results
mPFS: 18mo (400mg) vs 20mo (800mg), no significant difference
2-yr PFS: 41% vs 46%
mOS: 55mo vs 51mo, no significant difference
2-yr OS: 76% vs 72%
Best response: CR 5% vs 3%, PR 40% vs 42%, SD 21% vs 22%
Crossover after progression on 400mg: 133 crossed to 800mg/day; 31% of assessable patients achieved objective response (n=3) or stable disease (n=33); mPFS after crossover ~5mo, mOS after crossover ~19mo
2-yr PFS: 41% vs 46%
mOS: 55mo vs 51mo, no significant difference
2-yr OS: 76% vs 72%
Best response: CR 5% vs 3%, PR 40% vs 42%, SD 21% vs 22%
Crossover after progression on 400mg: 133 crossed to 800mg/day; 31% of assessable patients achieved objective response (n=3) or stable disease (n=33); mPFS after crossover ~5mo, mOS after crossover ~19mo
Adverse events
Hematologic: anemia more frequent on 800mg/day
Dermatologic / constitutional: rash and fatigue more frequent on the higher dose
Dose modification: more grade 3-4 toxicity and more dose reductions in the 800mg arm
Dermatologic / constitutional: rash and fatigue more frequent on the higher dose
Dose modification: more grade 3-4 toxicity and more dose reductions in the 800mg arm
Conclusions
High-dose imatinib (800mg/day) did not provide a clinically or statistically significant improvement over 400mg/day in metastatic GIST; dose escalation at progression gave modest disease control in a minority of patients.
Key Limitations
Permitted crossover from 400mg to 800mg confounds the OS comparison; mutation status not used for randomization, so any exon 9-specific dose effect is not captured; the crossover analysis is non-randomized and hypothesis-generating only.
Clinical Context
S0033, together with EORTC 62005, established 400mg/day as standard first-line imatinib for metastatic GIST and confirmed that dose escalation to 800mg is a reasonable option at progression. Pooled in MetaGIST, the higher dose benefits chiefly KIT exon 9-mutant tumors; ESMO/ASCO favor mutation-guided dosing.