EORTC 62005 trial

Background

Phase III RCT (EORTC/ISG/AGITG). 946 patients with advanced/metastatic GIST. Tested whether higher-dose imatinib improves outcomes over standard dosing in the first-line setting.

Interventions and follow up

Arm A: imatinib 400mg daily
Arm B: imatinib 400mg twice daily (800mg/day)
Primary endpoint: Progression-free survival (PFS)
mFollow up: 25mo

Results

2-yr PFS: 50% (800mg) vs 44% (400mg), HR 0.82, 95%CI 0.69-0.98, P=.026 favoring 800mg
1-yr OS: 86% vs 85%
2-yr OS: 74% vs 69%, no significant difference
Best response: CR 5-6%, PR 45-48%, SD ~32%, similar across arms
Crossover: of 473 assigned to 400mg, 247 progressed and 133 crossed over to 800mg/day

Adverse events

Hematologic: anemia more frequent on 800mg/day
Constitutional / GI: fatigue, edema, diarrhea, nausea more frequent on the higher dose
Dose modification: more dose reductions/interruptions in the 800mg arm

Conclusions

Response rates were similar, but 800mg/day modestly improved PFS over 400mg/day at the cost of more toxicity; benefit was later shown to concentrate in KIT exon 9-mutant tumors.

Key Limitations

PFS gain was small with no OS benefit; permitted crossover dilutes the dose comparison; mutation status not stratified at randomization, so the exon 9 benefit was identified only retrospectively; higher-dose toxicity limits routine use.

Clinical Context

Standard first-line imatinib for advanced GIST is 400mg/day. Pooled with US Intergroup S0033 in the MetaGIST analysis, the data support 800mg/day first-line specifically for KIT exon 9-mutant tumors, an approach endorsed by ESMO and reflected in ASCO guidance. Dose escalation to 800mg is an option at progression on 400mg.

References