2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TARGETED THERAPY IN SARCOMA
rates at 3- and 6-months were 70% and 34%, respectively,
with ridaforolimus compared with 54% and 23%, respectively,
with placebo. The “benefit rate” (CR, PR, and SD
lasting 4 months or longer) was 41% with ridaforolimus
versus 29% with placebo (p � 0.0009), and best target
response was a mean decrease of 1.3% with ridaforolimus
compared with a mean increase of 10.3% with placebo (p �
0.0001). A nonsignificant trend in OS was seen favoring
ridaforolimus (21.4 vs. 19.2 months, HR � 0.88, p � 0.23).
Although the results from this study suggest that mTOR
maintenance therapy may be considered an alternative to
the more traditional “watch and wait” approach, it is important
to consider associated adverse events (AEs) with this
medication. In the data presented, nearly two-thirds of
patients experienced at least 1 grade 3 or worse AE, including
stomatitis (9%), infection (6%), thrombocytopenia (10%),
anemia (7%), and hyperglycemia (7%). When considering all
grades of AEs in enrolled patients, 61% experienced stomatitis;
52% infections; approximately one-third of patients
experienced fatigue, thrombocytopenia, diarrhea, cough,
and rash; and approximately one-quarter of patients experienced
anemia, hypertriglyceridemia, and hypercholesterolemia.
Even though these numbers represent events
occurring in a minority of patients, the potential impact of
lesser grade 1 to 2 events occurring in the context of the
maintenance setting should not be overlooked and results
from quality-of-life questionnaires obtained as part of exploratory
analyses are anticipated.
In an effort to identify predictors of response to ridaforolimus,
additional exploratory analyses were performed and
recently reported. 5 Post hoc analyses revealed greater median
PFS in those patients who experienced grade 2 or worse
stomatitis compared with those who did not, or those who
received placebo. In addition, an analysis of the cohort of
patients with SD at study entry suggested an increased
benefit in those patients with truly stable or early growth
compared with those with minor responses.
The role of mTOR inhibition in the treatment of metastatic
sarcoma continues to be developed. Combination therapy
with conventional cytotoxics, as well as combination
with other targeted therapies, is being considered. Assessing
alternative pathway activation in mTOR inhibitor–resistant
disease will be important, and will likely guide future trials.
KEY POINTS
● Sarcomas are a rare, heterogeneous cancer in need of
new therapies.
● Clinical trials to date have focused largely on unselected
patient populations including multiple subtypes.
● A better understanding of the molecular mechanisms
driving the pathogenesis of sarcoma is needed.
● Clinical trials with integrated biologic correlatives
are more likely to identify subtypes likely to benefit
from targeted therapy.
● Collaboration between basic scientists and clinical
investigators is critical.
Angiogenesis Inhibition and Sarcomas
The use of antiangiogenic agents in sarcoma is not a new
concept. The mixed clinical results in cancer studies suggest
that the road to understanding the key elements of angiogenesis
and where one may safely intervene in the patient
with cancer is far from straightforward.
Recent focus has been on therapies directed against vascular
endothelial growth factor (VEGF) and its receptors
(VEGFRs). The combination of anti-VEGF monoclonal antibody
bevacizumab with doxorubicin was explored in a small
phase II study. 6 The combination was not obviously more
active than doxorubicin itself, and was associated with
toxicity. A more recent phase I study of gemcitabine and
docetaxel with bevacizumab showed a 31% RECIST (Response
Evaluation Criteria in Solid Tumors) response rate. 7
It is not clear whether this response rate reflects the activity
of the gemcitabine-docetaxel combination alone, or synergy
with bevacizumab. We hope this question will be answered
for leiomyosarcoma in a randomized phase III clinical trial
from the Gynecologic Oncology Group (clinicaltrials.gov
identifier NCT01012297) comparing gemcitabine and docetaxel
with or without bevacizumab. For angiosarcoma, the
situation may be slightly different, with greater RECIST
response rates (12%) observed for bevacizumab. 8
MTKIs have shown modest benefit in specific non-GIST
sarcomas as single agents, but their multitargeted nature
makes ascribing the activity of one kinase or another to the
growth of a specific sarcoma difficult. There are few data to
suggest that any MTKI has substantial activity in sarcomas
such as leiomyosarcoma or unclassified pleomorphic sarcoma/malignant
fibrous histiocytoma (UPS/MFH). The phase
II studies of sunitinib, sorafenib, and pazopanib yielded very
low RECIST response rates across an unselected patient
population. 9-12 Similar to bevacizumab, a higher response
rate (14%) for sorafenib was observed in angiosarcomas.
Nonetheless, MTKIs may have measurable activity, as
demonstrated in a randomized clinical trial of pazopanib
compared with placebo in advanced soft tissue sarcoma
subtypes. 13 The PALETTE (Pazopanib Explored in Soft-
Tissue Sarcoma) study explored 369 patients randomly
assigned to receive pazopanib 800 mg daily or placebo until
disease progression. Median PFS was 20 weeks for pazopanib
compared with 7 weeks for placebo (HR � 0.31, p � 0.0001). An
interim analysis showed a nonsignificant improvement in
median OS for pazopanib (11.9 vs. 10.4 months, HR � 0.83,
p � 0.18), in this study with a cross-over design.
Similarly, specific sarcoma subtypes may demonstrate
sensitivity to antiangiogenic agents. In addition to angiosarcoma
and VEGF inhibitors, alveolar soft-part sarcoma can
respond to VEGFR inhibitors cediranib 14 or sunitinib, 15 and
solitary fibrous tumors demonstrate at least hints of activity
to sunitinib 16 or the combination of bevacizumab and temozolomide.
17 The precise mechanism of antiangiogenic agents
in these sarcoma subtypes remains unknown.
If mTOR can be construed to be a proangiogenic kinase, 18
then the results of phase II and phase III studies are
less-than-convincing evidence for the use of first-generation
mTOR inhibitors as antiangiogenic agents. 19 These agents
do not inhibit the reflex activation of Akt by mTOR complex
TORC2 that is common to all presently available allosteric
TORC1 complex inhibitors. As a result, newer direct TORC1
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