2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Targeted Therapy in Sarcoma: Should We Be
Lumpers or Splitters?
By Richard F. Riedel, MD, Robert G. Maki, MD, PhD, and Andrew J. Wagner, MD, PhD
Overview: The identification of KIT as a critical driver in the
pathogenesis of GI stromal tumor (GIST), and its subsequent
inhibition with imatinib, have resulted in tremendous efforts to
identify other potential therapeutic targets for the heterogeneous
group of diseases known as sarcomas. Because of the
rarity of sarcoma and the often limited number of patients per
individual sarcoma subtype, clinical trials to date have often
utilized unselected patient populations including multiple subtypes.
Although this strategy increases the ease with which a
particular trial may accrue patients, statistically significant
therapeutic responses across an unselected patient popula-
SARCOMAS REPRESENT a diverse group of mesenchymal
neoplasm affecting approximately 13,000 individuals
each year. 1 The treatment of advanced disease is
particularly challenging because of the limited number of
effective systemic therapies. As a result of the success of
tyrosine kinase inhibitors (TKIs), such as imatinib in the
management of GIST, investigation of other targeted therapies
for this rare group of diseases has become an active
and ongoing area of research. Some of the most active
investigations have centered on inhibiting angiogenesis as
well as the phosphoinositide 3-kinase (PI3K), Akt/mammalian
target of rapamycin (mTOR), and insulin-like growth
factor 1 receptor (IGF1R) oncogenic pathways. Although a
number of multitargeted TKIs (MTKIs) and pathwayspecific
therapies have been explored, response rates have
generally been disappointing and few have been investigated
in the phase III setting.
Whereas a mesenchymal origin is shared between histologic
subtypes of sarcoma, the molecular drivers of tumor
initiation, growth, and maintenance are more varied and
complex. Critical to our success in further understanding
the key signals and pathways that drive pathogenesis is
active communication between basic scientists and clinical
investigators. Although the traditional knowledge flow has
been from the laboratory to the clinic, observations noted
from clinical trials have, in fact, created fertile ground for
scientific exploration and discovery in the laboratory setting.
This review will highlight recent data from both the
laboratory and clinical settings, including recently reported
phase III studies, to support the ongoing investigation of
targeted therapies in the of patients with sarcoma. In
addition, the rationale behind the use of specific therapies in
more targeted populations of patients, with specific attention
to unique sarcoma subtypes, will be provided.
Targeted Therapy in Unselected Subtypes
Because of the rarity of sarcoma and the desire to accrue
patients in a timely fashion, prospective clinical trials have
traditionally been more encompassing rather than more
restrictive with respect to the inclusion of histologic subtypes.
The result is often a mixture of histologies i n different
proportions from one study to the next, including
translocation-associated (e.g., synovial sarcoma) and aneuploid
subtypes (e.g., leiomyosarcoma and undifferentiated
pleomorphic sarcoma), with heterogeneous biologic mecha-
652
tion are often limited. Furthermore, in the absence of biologic
correlatives, the identification of significant activity and subsequent
interpretation of clinical trial results utilizing targeted
therapies for this patient population have been challenging.
However, hints have emerged, on the basis of preclinical and
clinical observations, to suggest that certain targeted therapeutic
approaches are appropriate in select histologic subtypes.
This brief review will highlight data supporting the use
of targeted therapy in both unselected and selected sarcoma
patient populations.
nisms driving their formation and growth. To date, the most
robust areas of investigation have included therapies targeting
mTOR, angiogenesis, and IGF1R.
mTOR Inhibition and Sarcomas
The mTOR pathway plays an important role in cell growth
and proliferation and is an active target for developing
cancer therapeutics. Activation of the mTOR pathway has
been identified in a number of human cancers, including
sarcoma. 2 A variety of mTOR inhibitors have been developed
and are in active investigation.
A phase II study of ridaforolimus, a nonprodrug rapamycin
analog, in 212 heavily pretreated patients with advanced
soft tissue and bone sarcomas was reported. 3 Patients received
ridaforolimus 12.5 mg intravenously once daily for 5
days every 2 weeks. A “benefit rate” of 29% (complete
response [CR], partial response [PR], or stable disease [SD]
lasting 16 weeks or longer) with five PRs was observed. The
median progression-free survival (PFS) and overall survival
(OS) were 15.3 and 40 weeks, respectively.
An oral formulation of ridaforolimus was also developed
and subsequently moved into the clinical trial setting as part
a maintenance strategy in sarcoma. Initial results from the
randomized, multicenter, phase III SUCCEED (Sarcoma
Multi-Center Clinical Evaluation of the Efficacy of Ridaforolimus)
trial were reported at ASCO’s 47 th Annual Meeting
(June 4–8, 2011, Chicago, IL). 4 Patients with advanced soft
tissue or bone sarcomas were randomly assigned 1:1 to
receive oral ridaforolimus (40 mg daily for 5 days each week)
or placebo as a maintenance approach in the setting of SD or
responsive disease after at least four cycles but no more than
12 months of chemotherapy. This was one of the largest
randomized controlled trials performed in sarcoma to date
and included over 700 patients. Median PFS, the primary
outcome of interest, was 17.7 weeks with ridaforolimus
compared with 14.6 weeks with placebo (hazard ratio [HR]
� 0.72, p � 0.0001), as assessed by independent review. PFS
From the Duke Cancer Institute, Duke University Medical Center, Durham, NC; Mount
Sinai School of Medicine, New York, NY; Dana Farber Cancer Institute, Boston, MA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Richard F. Riedel MD, Box 3198 DUMC, Durham, NC 27710;
e-mail: richard.riedel@duke.edu.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10