2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TKI-RESISTANT GIST
Primary Imatinib Resistance
Approximately 10% of treated GIST patients experience
primary tumor resistance to imatinib therapy. The most
common cause of early imatinib resistance is a primary
resistance mutation in PDGFRA or KIT. 13 KIT exon 9
mutations have decreased in vitro sensitivity to imatinib,
and larger clinical doses of imatinib may be required to
achieve a response. 10 Therefore, early progression on 400 mg
of imatinib is common for patients with KIT exon 9 mutant
GIST. In addition, the most common PDGFRA mutation,
D842V, is strongly resistant to imatinib in vitro. This
mutation changes the receptor to the active conformation to
which imatinib cannot bind. Recently, mutations of downstream
signaling pathways (KRAS, BRAF, or PIK3CA) have
been reported to coexist with KIT mutations in a minority of
patients. These mutations could reduce or eliminate the
efficacy of upstream KIT inhibition by maintaining signaling
through KIT-dependent downstream signaling pathways. 3
Wild-type GISTs (i.e., no KIT or PDGFRA mutation) also
have a higher rate of primary resistance to imatinib than
the typical KIT exon 11-mutant GIST. The rate of response
likely correlates with the underlying molecular defect, but
definitive genotype/outcome data are not available. For
instance, BRAF exon 15 mutations have been found in this
wild-type group, and these mutations are not sensitive to
imatinib. Additionally, those GISTs with abnormalities in
the SDH complex appear to be less responsive to imatinib. 3
In addition to the effect of the underlying tumor biology,
there is controversy about whether a threshold drug level
of imatinib is needed to see a response in GIST. There is no
prospective data looking at the proper imatinib levels
needed to achieve a response in GIST. However, in a
retrospective subgroup analysis of one of the phase II
studies, a minimum trough level of 1,100 ng/mL of imatinib
was required for optimal results. 14 However, the utility of
imatinib levels to adjust dosing remains unproven.
Secondary Imatinib Resistance
Eventual progression of disease is an issue for the vast
majority of patients treated with imatinib. This is likely due
to expansion of GIST clones with secondary kinase mutations.
15 Secondary KIT or PDGFRA mutations have only
been found in patients who had a primary mutation, that is,
not in wild-type patients. In addition, the secondary mutations
occur in the same gene and on the same allele (in cis)
as the primary mutation. 15 Tumors with a primary exon 11
mutation are the most likely to develop a secondary KIT
mutation. In the above mentioned U.S.-Finnish phase II
trial of imatinib, two-thirds of patients with progression on
imatinib were found to have secondary mutations in one or
more post-treatment samples. These secondary mutations
occur primarily in the activation loop (exons 17 and 18) or
ATP binding pocket (exons 13 and 14). The situation is
further complicated by multiple studies demonstrating significant
intra- and interlesional heterogeneity of secondary
mutations. 16 In vitro profiling of alternative KIT/PDGFRA
TKIs (e.g., sunitinib) has shown that most inhibitors lack
activity against all relevant secondary mutations. Thus
heterogeneity of resistance mutations in imatinib-resistant
GIST can result in differential responses of lesions to
second- or third-line TKIs. In addition to complicating rou-
tine clinical care, this situation also can obscure the potential
benefit of new agents tested in clinical studies.
With respect to the model of GIST stem and progenitor
cells discussed above, secondary resistance is due to the
appearance of clones with secondary mutations. These
clones could arise from either stem/progenitor cells or from
more differentiated cell populations. It is yet unclear if these
secondary, more resistant, kinase mutations are acquired
during drug therapy, or pre-exist and simply expand under
the selective pressure of TKI therapy.
Second-Line TKI Therapy
For patients with documented primary or secondary
imatinib-resistant GIST, the suggested initial intervention
is to increase the dose of imatinib to 800 mg if the patient is
on a lesser dose. Most patients will not benefit from imatinib
dose escalation, with a median PFS following dose increase
of only 3 months. However, 15% to 25% of patients may have
more prolonged responses that can last for many months or
years. 9 This may be due to inadequate drug levels with the
original dose or in some cases may be due to overcoming
secondary mutations with the higher imatinib dose.
If there is progression on the 800 mg dose of imatinib or if
the patient cannot tolerate the 800 mg total daily dose, the
next FDA-approved treatment is to switch to sunitinib. In a
phase III study, sunitinib-treated patients had a median
time to progression of disease of 27.3 weeks compared with
6.4 weeks with placebo. 17 These results were obtained using
the typical sunitinib dosing schedule of 50 mg daily for 4
weeks with 2 weeks off. Notably, a phase II trial of continuous
daily dosing of sunitinib at 37.5 mg produced a similar
time to progression at 34 weeks. 18 Therefore, given better
tolerability, many GIST experts will recommend starting
patients on continuous daily dosing of sunitinib.
Because sunitinib was the first medication to be tested in
the imatinib-resistant population, it was the first to get FDA
approval. However, with our increased understanding about
secondary KIT and PDGFRA mutations, it is clear that the
range of activity of sunitinib against these secondary mutations
is suboptimal. Sunitinib has substantial activity
against secondary mutations in exons 13 and 14, but cannot
inhibit kinase activity in the presence of mutations in exons
17 or 18. 19 Given that there is approximately equal frequency
of these secondary mutations in most series, and the
aforementioned heterogeneity of secondary mutations in a
given patient, it is common to see mixed responses during
sunitinib therapy. Sunitinib, unlike imatinib, has activity
against VEGFR1/2. 20 However, it appears that most of the
activity addition of this agent against imatinib-resistant
GIST is due to inhibition of KIT rather than inhibition of
angiogenesis.
Third-Line Therapy (And Beyond)
Following progression on sunitinib, the optimal next step
in therapy is unclear. Multiple TKIs have been studied in
this setting, but there has yet to be a clear best therapy for
imatinib- and sunitinib-resistant GIST. Therefore, patient
participation in a clinical study should be strongly considered
in this setting. 20
There are multiple drugs being tested in clinical trials
that directly or indirectly target KIT, KIT-dependent signaling
(e.g., MEK or PI3K), or more remote downstream events
665