2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

and TORC2 inhibitors could potentially demonstrate greater
activity as antiangiogenic compounds.
Other antiangiogenic agents have shown hints of activity
in sarcomas and other cancers, without convincing survival
improvement. The thrombospondin mimetic ABT-510 demonstrated
only one RECIST PR in 82 patients receiving
treatment, although time to progression suggested some
activity of the compound. 20 Vascular-disrupting agent combretastatin
A4, a tubulin antagonist and antiangiogenic
agent, showed only modest clinical activity as a single agent
and in combination with cytotoxic chemotherapy agents in
phase I studies, although it appeared to have biologic effects
by dynamic contrast-enhanced magnetic resonance imaging
and other correlative studies. 21,22 New derivatives of combretastatin
are being examined preclinically as well as in
phase I studies. A newer approach involves targeting of
other kinases involved in angiogenesis, including TIE1 and
TIE2, with monoclonal antibodies, peptide-antibody conjugates,
or small molecules, some of which have reached phase
I clinical trials.
Targeted Therapy in Selected Subtypes
Although the clinical classifications of sarcomas can provide
prognostic and predictive information, they rarely include
the emerging molecular biologic data that may lead to
advances in tumor-specific treatments. Several findings
from laboratory-based studies have recently been brought to
clinical investigation in specific sarcoma subtypes for which
there are few known effective therapies. Although the true
efficacy of these novel approaches is still unknown, the
pairing of genetic and biochemical alterations with targeted
therapies has generated proof-of-concept evidence of activity
in laboratory and early clinical settings.
IGF1R Inhibition in Ewing Sarcoma
IGF1R has been recognized as a viable target for treatment
of pediatric sarcomas for 20 years. 23 For example, the
role of IGF1R signaling to maintain activity of the Ewing
sarcoma EWSR1-FLI1 translocation product indicated that
blockade of this pathway would consistently block Ewing
sarcoma growth. It was not until there was availability of
agents more potent than somatostatin analogs at blocking
the IGF1R signaling axis that there has been an opportunity
to examine this hypothesis. In what is a common story
regarding the sophistication of cancer, IGF1R blockade,
which appeared to be nearly a perfect tumor-specific target
in Ewing sarcoma, has become a more complicated story.
The avalanche of data regarding Ewing sarcoma and
IGF1R inhibitors has come from the observation of responses
from limited number of patients in the phase I
development of the monoclonal antibodies targeting the
receptor. Despite differences in specific antibody characteristics,
a consistent RECIST response rate has been observed.
For example, AMG479 IV every 2 weeks yielded a long-term
RECIST CR and one PR in Ewing sarcoma and a PR in a
patient with a neuroendocrine tumor, although 10 other
Ewing sarcoma patients did not experience response. 24 Two
of 13 assessable patients with Ewing sarcoma experienced
RECIST PR while receiving intravenous figitumumab in a
phase I expanded cohort study; others showed disease
shrinking but did not experience PR. 25 A phase I/II study of
cixutumumab in a pediatric population showed two (10%) of
654
RIEDEL, MAKI, AND WAGNER
20 patients with a RECIST PR at the highest dose studied (9
mg/kg/week), but the median PFS for this cohort was
slightly longer than 6 weeks. 26
Further study of figitumumab in a pediatric Ewing sarcoma
population (10 to 18 years) in the phase II portion of a
phase I/II study demonstrated a 14% RECIST response rate
(15 PR in 106 patients). 27 In this study, a higher baseline
total or free IGF1 level was associated with longer survival
than was low baseline free or total IGF1. A population of
patients with very high baseline IGF1 fared as poorly as
those with the lowest levels of IGF1, however. A similar
phase II study performed with IGF1R monoclonal antibody
yielded a RECIST response rate of 10% (11 of 115 patients,
10 of whom had had a bony primary site). 28 In addition,
among patients with IGF1 samples available at week 6 of
the study, total serum IGF1 greater than 110 ng/mL at 6
weeks of therapy and a greater proportional increase in total
IGF1 from baseline to week 6 both predicted for improved
survival.
The rapid development of progressive disease observed in
some patients, after evidence of early treatment benefit, 29,30
speaks against the development of secondary mutations in
IGF1R. Other mechanisms of resistance include heterodimerization
with other receptor tyrosine kinases 31 and
nuclear translocation of adapter proteins such as IRS1, 32,33
and IGF1R itself, which is mediated by SUMOylation, a
post-translational modification. 34 The low but consistent
response rate seen for IGF1R inhibitors increases our appreciation
for the multiple levels of regulation that exist to
ensure cellular homeostasis. At the same time, new mechanisms
complementary to kinase blockade are needed to yield
better combinations of anticancer therapeutics.
ALK Inhibition in Inflammatory Myofibroblastic Tumors
Inflammatory myofibroblastic tumors (IMTs) are a rare
subset of sarcomas of intermediate biologic potential with a
predilection for local recurrence and, much less commonly,
metastasis. 35 Recurrent cytogenetic alterations involving
the short arm of chromosome 2 and immunohistochemical
overexpression of the ALK gene that resides in this chromosome
36 has led to the identification of translocations of ALK
in approximately 50% of IMTs. 37 In IMTs, ALK encodes a
receptor tyrosine kinase that can be fused to one of at least five
other gene partners. ALK expression in IMT reliably predicts
ALK gene rearrangement. Tumors without ALK rearrangement
appear to have a higher propensity for distant
metastases without an increased risk of local recurrence. 38
Chromosomal translocations of ALK have been identified
in a subset of non–small cell lung cancer (NSCLC), 39 and
point mutations in ALK have been reported in neuroblastoma.
40 The discovery of activating structural rearrangements
and point mutations among different lineages
strongly supported the oncogenic role of ALK, which was
corroborated in a variety of in vitro models as well. Concurrent
with many of these discoveries was the early-phase
clinical development of crizotinib (formerly PF-02341066),
an orally administered inhibitor of the MET and ALK
tyrosine kinases. Dramatic clinical activity was observed in
patients with ALK-rearranged NSCLC 41 ultimately leading
to regulatory approval for this indication.
Two patients with IMTs were enrolled in a phase I study
of crizotinib. 42 A sustained PR was observed in a patient
with an ALK-rearranged tumor, whereas no activity was