Biomedical Engineering Reference
In-Depth Information
resulting in significantly longer progression-free survival and higher
objective response rate [130].
In the treatment of advanced GIST, mutational status has prog-
nostic importance and may also be predictive of response to TKI
therapy. The National Comprehensive Cancer Network (NCCN) cur-
rently recommends initial dosing of imatinib and 400 mg once daily
in patients with unresectable or advanced GIST. However, for those
patients with a known exon 9 mutation, NCCN supports the use of
higher imatinib dose at 800 mg daily. In comparison, the European
Society of Medical Oncology (ESMO) recommends routine use of
mutational testing for all patients with advanced GIST and use of
imatinib at an initial dose of 800 mg daily for those patients whose
tumors harbor exon 9 mutation [99, 131].
9.4.4.2 Imatinib plasma levels
The occurrence of adverse events correlates with free plasma levels
of imatinib. It has been reported that significant variability in plasma
imatinib area under the curve (AUC) levels was observed in patients
who did not develop significant side effects than those who did [132].
The inter-patient variability in imatinib pharmacokinetic exposure
may explain the lack of benefit with higher doses of imatinib. Higher
imatinib AUC predicted for better response to imatinib with the
strongest association seen in patients whose tumors harbor exon 9
mutation or wild-type KIT [133].
In the previously described B2222 trial, clinical outcome was
correlated with plasma imatinib trough levels in 73 patients in
whom plasma trough levels were available at the start of therapy
and at steady state. The patients were grouped into quartiles of
imatinib plasma trough levels. A high interpatient variability in
imatinib pharmacokinetic exposure was observed. The median time
to progression was 11.4 months for patients in the lowest trough
level quartile compared with more than 30 months for those in the
other three quartiles. The overall objective benefit rate (complete
response, partial response, and stable disease) was also lower in
the lowest quartile. A mutation in
exon 11 was associated with
overall objective benefit rate of 67% for the lowest quartile versus
100% for the other quartiles [134]. In a small population-based
trial, low imatinib trough levels were also reported in prior major
gastrectomy, increased creatinine clearance, and high serum albumin
levels [135]. The variability in free plasma levels of imatinib may
KIT
