Biomedical Engineering Reference
In-Depth Information
The investigators of the phase III clinical trial EORTC 62005
analyzed pre-treatment samples of GISTs from 377 patients to
determine if tumor mutational status correlates with response to
imatinib. The strongest negative predictive factor for response to
imatinib was found to be the presence of exon 9 mutations in
KIT
.
The relative risk of progression was increased by 171% (
p
< 0.0001)
and the relative risk of death by 190% (
< 0.0001) when compared
with KIT exon 11 mutants. Additionally, treatment with the high-
dose regimen resulted in a significantly superior progression-
free survival (
p
= 0.0013), with a reduction of the relative risk of
61% in patients with an exon 9
p
KIT
mutation. In patients without
detectable
KIT
or
PDGFRA
mutations, the relative risk of progression
was increased by 108% (
p
< 0.0001) and the relative risk of death
by 76% (
= 0.028). The authors concluded that tumor genotype
carries major prognostic importance for progression-free survival
and overall survival in patients with advanced GIST treated with
imatinib [129].
The SWOG S0033/CALGB 150105 trial confirmed the findings of
the B2222 and EORTC 62005 trials demonstrating that
p
exon 11
mutations are associated with more favorable outcome compared
with
KIT
exon 9 mutations or wild-type GIST. The objective response
rates for
KIT
exon 11 mutations, KIT exon 9 mutations or no
detectable kinase mutation were 84%, 48% and 0%, respectively.
Longer time to disease progression was also observed in patients
with
KIT
exon 11 mutations (25 vs. 17 vs. 13 months, respectively).
The median overall survival was 60 months versus 38 months versus
49 months, respectively. Although the response rate was better with
high-dose imatinib in patients with
KIT
exon 9 mutations, unlike the
EORTC trial, there was no demonstrable improvement in PFS with
high dose compared with standard dose imatinib [95].
The Gastrointestinal Stromal Tumor Meta-Analysis Group
(MetaGIST) analyzed the data from EORTC 62005 and SWOG S0033/
CALGB 150105 comparing the two doses of imatinib (400 mg
vs. 800 mg per day) in 1,640 patients. The study end-points were
progression-free survival and overall survival. At a median follow-up
of 45 months, a small but significant progression-free survival was
observed in the 800 mg arm. The overall survival was not different
between the two treatment arms. Overall, the presence of
KIT
exon
9 mutations was predictive for PFS benefit to high dose imatinib
KIT
