2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

defect in most cases of renal cell carcinoma). In addition, loss
of SDHB protein expression is seen in pediatric GISTs and
some GISTs with pediatric features that arise in adult
patients. The underlying molecular defect in these wild-type
GISTs likely has significant influence on the response (or
lack thereof) to TKI therapy.
Initial Treatment with TKIs
Before 2000, patients were treated with conventional
chemotherapy, resulting in very poor response rates and no
effect on overall survival. In 2000, this situation was dramatically
altered by the first trials of TKI therapy for
advanced or unresectable GIST.
Imatinib was originally developed as a treatment for
chronic myelogenous leukemia (CML). The fusion protein
BCR-ABL is the target for imatinib in CML, 5 and the
knowledge that ABL is structurally similar to KIT led to
preclinical investigation of the ability of imatinib to inhibit
KIT signaling. 6 In these studies, imatinib was shown to
inhibit both wild-type and mutant KIT protein, including
KIT exon 11 or 13 mutations that are found in GIST. 6,7 In
addition, imatinib was also found to inhibit PDGFRA/B
kinase activity.
Based in part on these preclinical studies, imatinib was
used to treat a single patient with widely metastatic disease.
Based on the remarkable tumor response in this patient,
imatinib was further tested in a phase I study of patients
with GIST or other soft tissue sarcoma. In the European
Organisation for Research and Treatment of Cancer
(EORTC) phase I study, 36 patients with GIST were treated
with imatinib doses ranging from 400 to 800 mg. 8 Notably,
only four patients demonstrated progressive disease; all
others demonstrated response or stable disease (by RECIST
criteria).
This very successful phase I trial lead to two phase II
trials, one by the EORTC and another by a U.S.-Finnish
group. 9 Both trials compared doses of 400 mg compared with
600 mg of imatinib. Overall, 89% of patients in the EORTC
trial and 87% of patients in the U.S.-Finnish trial had stable
KEY POINTS
● Imatinib is the front-line treatment for patients with
unresectable or advanced GIST.
● Primary imatinib resistance is usually related to the
pretreatment biology of the GIST and is more common
in patients whose tumor has one of the following
genotypes: wild-type, KIT exon 9-mutant, or PDG-
FRA D842V.
● Secondary imatinib resistance is typically due to the
expansion of tumor clones with acquired kinase mutations
that confer drug resistance.
● Sunitinib treatment is indicated for patients with
imatinib intolerance and/or imatinib-resistant tumors.
● The optimal treatment for patients with sunitinibresistant
tumors is unknown. Treatment options include
participation in a clinical study, off-label use
of other KIT tyrosine kinase inhibitors, or palliative
surgery.
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disease or partial response as their best response to therapy.
One notable difference between the trials was that patients
in the U.S.-Finnish trial were allowed to cross over to the
600 mg arm if they progressed on 400 mg. 30% of patients
who progressed on the 400 mg dose who crossed over to the
600 mg dose obtained a partial response or stable disease
status.
Following these pivotal trials, two phase III trials were
performed, both similarly designed with the intent to combine
them into a meta-analysis. 10 These trials compared 400
mg daily with 800 mg daily of imatinib. Both trials allowed
cross-over to 800 mg on progression during treatment with
400 mg per day of imatinib. In EORTC 62005, only 18% of
patients had progressive disease, while in the S0033 study
26% of patients had progressive disease as the best response
to treatment. In the Meta-GIST analysis of these two studies,
there was a small progression-free survival (PFS) seen
with the 800 mg dose of imatinib, but this was almost
exclusively due to the superior results seen with the higher
dose among patients with KIT exon 9-mutant GIST. In
contrast, there was no improvement in PFS for GISTs with
non–exon-9 mutations treated with high-dose imatinib. Notably,
there was no improvement in overall survival in
patients treated with high-dose imatinib.
Disease Persistence
Despite high rates of response, it appears that continuous
therapy is required for optimal disease control. A randomized
study of patients who had disease control after 3 years
of imatinib demonstrated a high rate of progression following
interruption of treatment. 11 The 2-year PFS was only
16% in those who stopped imatinib compared with 80% in
patients who continued on imatinib.
So why doesn’t TKI therapy completely eradicate (cure)
GIST? There is evidence that unlike mature GIST cells,
GIST stem and progenitor cells are immune to KIT inhibition.
3 Therefore, KIT inhibitors such as imatinib can inhibit
and potentially kill mature cells, but a pool of quiescent stem
and progenitor cells will remain. With cessation of treatment,
this pool can relatively quickly repopulate tumors
with differentiated GIST cells. This phenomenon is referred
to as disease persistence and is distinct from clinical resistance
that is discussed below.
Imatinib Resistance
BARNETT AND HEINRICH
Based on the phase II studies, imatinib was approved by
the U.S. Food and Drug Administration (FDA) for first-line
treatment of advanced GIST. Despite these promising results,
treatment with imatinib is not curative and GIST
lesions can develop drug resistance after varying intervals of
time. Resistance to imatinib can be divided into two types,
primary resistance for the tumors that progress within the
first 6 months of imatinib treatment, and secondary resistance
in tumors that progress after this period. Notably,
distinct molecular mechanisms are associated with primary
versus secondary resistance.
The median PFS on front-line imatinib is in the range of
20 to 24 months. In the U.S.-Finnish phase II study cited
above, approximately 18% of patients remain on front-line
imatinib a decade later. Thus, the majority of imatinibtreated
patients will eventually develop resistant disease. 12