2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 1. Investigational Therapies in GIST
Drug Type Drug Target(s) Trial Information
Tyrosine kinase
inhibitors
Imatinib KIT, PDGFR FDA approved
Sunitinib KIT, PDGFR, VEGFR FDA approved
Nilotinib KIT, PDGFR Phase III
NCT00785785
Dasatanib KIT, PDGFR Phase II
NCT00568750
Sorafenib KIT, PDGFR, VEGFR Phase II
NCT01091207
Regorafenib KIT, PDGFR, VEGFR Phase III
NCT01271712
Vatalanib KIT, PDGFR, VEGFR Phase II
NCT00117299
Masitinib
(AB1010)
KIT, PDGFR Phase III
NCT00812240
Pazopanib KIT, PDGFR, VEGFR Phase II
NCT01323400
Crenolanib PDGFR Phase II
NCT01243346
Dovitinib VEGFR, PDGFR, FGFR Phase II
NCT01478373
HSP90 inhibitors STA-9090 HSP90 Phase II
NCT01039519
AT-13387 HSP90 Phase II
NCT01294202
AUY922 HSP90 Phase II
NCT01404650
Monoclonal
antibody
IMC-3G3
(Olaratumab)
PDGFR Phase II
NCT01316263
Bevacizumab VEGFR Phase III
NCT00324987
mTOR inhibitor Everolimus mTOR Phase II
NCT00510354
Miscellaneous Perifosine AKT (PI3K pathway) Phase II
NCT00455559
BKM120 PI3K pathway Phase I
NCT1468688
TH-302 Tumor hypoxia Phase I
NCT01381822
(histone deacetylase inhibitors). These medications are
sometimes used in combination with KIT inhibitors. For
example, multiple heat shock protein 90 (Hsp90) inhibitors
are in phase II trials in GIST. Hsp90 is an important
chaperone protein for oncoproteins such as KIT. Inhibition
of this target leads to preferential degradation of activated
forms of KIT (as well as other activated kinases). There is
strong preclinical data showing that Hsp90 inhibitors have
activity against imatinib-resistant GIST in vitro; 21 however,
there is not yet strong clinical data for the use of these
medications in GIST. In addition, there is evidence to
suggest that the downstream PI3K-mTOR pathway is perhaps
the most important signaling pathway in GIST 3 and
inhibitors of this pathway including everolimus, BKM120,
and perifosine are currently in phase II clinical trials (Table
1). In addition to clinical strategies to inhibit downstream
pathways, multiple TKIs are currently in trials for TKIresistant
GIST. Of note, a novel agent, crenolanib, is being
tested in a phase II study for treatment of PDGFRA D842Vmutant
GIST. As noted above, this particular mutation is
strongly resistant to imatinib (and sunitinib as well). 22
In terms of FDA-approved KIT/PDGFRA kinase inhibitors,
a number of these have been tested in phase II studies
of drug-resistant GIST. For example, nilotinib has been
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studied in a several clinical studies against drug-resistant
GIST. 23 Nilotinib is structurally very similar to imatinib
and, like sunitinib, lacks the ability to overcome any of the
activation loop mutations in exons 17 or 18. In addition, like
imatinib, it also has limited potency against ATP binding
pocket mutations. Because of this, nilotinib has shown
limited activity in imatinib- and sunitinib-resistant GIST.
In a phase III trial, 248 patients were randomly assigned to
nilotinib versus best supportive care for third-line therapy.
24 There was no statistical difference in overall survival
between nilotinib and best supportive care. Sorafenib has
more promising data for treatment of drug-resistant GIST,
with an approximate 20-week PFS in the third-line, and
even fourth-line setting. 25 This may be due to its apparent
ability to overcome some exon 17 mutations in vitro. However,
it appears that this agent has been supplanted in
clinical development by its closely related analog, regorafenib.
In a recent phase II trial, regorafenib showed a
promising 10-month PFS in the third- or fourth-line setting.
26 Based on these results, a randomized, double-blind,
placebo-controlled phase III study was initiated for patients
who were intolerant of or who had progression during prior
first- and second-line therapy. The study completed enrollment
in mid-2011 and the final study analysis is planned for
sometime in early 2012.
The National Comprehensive Cancer Network guidelines
suggest consideration of a clinical study or off-label treatment
with sorafenib, nilotinib, or dasatinib for physicians
with patients with imatinib- and sunitinib-resistant GIST. 20
In addition, reintroduction of imatinib can be considered.
Fumagalli and colleagues have published data supporting
rechallenging patients with imatinib or sunitinib after failure
of standard and investigational agents. 27 Most GIST
experts believe that life-long continuation of TKI therapy
should be considered an essential component of best supportive
care. As noted above, GIST patients often harbor
deposits of quiescent, drug-sensitive tumor cells that will
become clinically active following discontinuation of TKI
therapy. These lesions can add to overall disease burden and
patient symptoms. In addition, there is evidence to suggest
that some secondary drug resistance mutations result in
relative rather than absolute resistance to TKI therapy;
continued TKI treatment may slow (but not arrest) such
clones, potentially palliating symptoms.
Role of Surgery in Advanced GIST
BARNETT AND HEINRICH
Given that there can be significant heterogeneity in secondary
mutations and therefore mixed responses with TKI
treatment of advanced GIST, many patients inquire about
surgery to control their disease. Raut and colleagues published
a study about their series of 69 patients who underwent
surgery while receiving TKI therapy, with the majority
receiving front-line imatinib (but a minority on second-line
sunitinib). Notably, only those patients with overall stable
disease (i.e., disease controlled by TKIs) strongly benefited
from surgery in terms of disease control (Table 2). 28 In
another study, 50 patients receiving second-line sunitinib
underwent surgery for their disease and median PFS was a
mere 5.8 months, and was independent of the immediate
presurgical sunitinib clinical response status. That is,
sunitinib-responding patients did not have better PFS after
surgery than patients with frank progression on sunitinib
before surgery. 29 In addition, over half of the patients had