Background
Phase II randomised controlled trial; pivotal for FDA approval (B2222). N=147 with Kit-positive (CD117+) advanced GIST, age ≥18 yr, not amenable to surgery/radiotherapy or standard cytotoxic therapy; 13 US centres, 2000-2001. Pre-trial, no effective systemic therapy existed (median survival <12 mo, GIST considered chemotherapy-resistant). Imatinib mesylate (STI571) is a selective TKI targeting Kit, PDGFRA, BCR-ABL. Built on the Joensuu et al (NEJM 2001) single-patient case report.
Interventions and follow up
Arm A: Imatinib mesylate 400 mg PO once daily until progression or intolerance
Arm B: Imatinib mesylate 600 mg PO once daily until progression or intolerance
Primary endpoint: Objective response rate
mFollow up: ~6 mo (initial report) with subsequent long-term follow-up
Arm B: Imatinib mesylate 600 mg PO once daily until progression or intolerance
Primary endpoint: Objective response rate
mFollow up: ~6 mo (initial report) with subsequent long-term follow-up
Results
ORR (combined): 53.7% (all partial responses; no complete responses at initial assessment)
ORR (400 mg): 54.8%
ORR (600 mg): 56.8% — no significant difference between doses
Stable disease: 27.9% (combined)
Disease control rate: 83.7% across both arms
ORR (400 mg): 54.8%
ORR (600 mg): 56.8% — no significant difference between doses
Stable disease: 27.9% (combined)
Disease control rate: 83.7% across both arms
Adverse events
Overall tolerability: well tolerated
Grade 3-4: oedema/periorbital oedema, nausea, diarrhoea, fatigue, neutropenia
Grade 3-4 haemorrhage: notable (intratumoral haemorrhage in responding lesions)
Skin rash: common
Dose effect: no dose-response for toxicity between 400 and 600 mg overall, though grade 3-4 rates higher with 600 mg
Grade 3-4: oedema/periorbital oedema, nausea, diarrhoea, fatigue, neutropenia
Grade 3-4 haemorrhage: notable (intratumoral haemorrhage in responding lesions)
Skin rash: common
Dose effect: no dose-response for toxicity between 400 and 600 mg overall, though grade 3-4 rates higher with 600 mg
Conclusions
Imatinib produced durable objective responses in 53.7% of advanced Kit-positive GIST — unprecedented in a historically chemotherapy-resistant disease — with no significant efficacy difference between 400 and 600 mg, establishing 400 mg once daily as standard. B2222 transformed GIST management and supported accelerated FDA approval in 2002.
Key Limitations
Phase II with no untreated/placebo control (ethically infeasible given prior chemoresistance), so survival benefit inferred against historical controls. Short initial ~6-mo follow-up; surrogate ORR endpoint. KIT/PDGFRA genotype-dependent response not characterized in this early report.
Clinical Context
Landmark trial establishing imatinib 400 mg daily as first-line standard for advanced/metastatic GIST per ESMO, with KIT/PDGFRA genotyping now guiding dosing (e.g., 800 mg for KIT exon 9). Sunitinib and regorafenib follow at progression; the imatinib paradigm extended to adjuvant therapy in high-risk resected GIST.