2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

EVOLVING TREATMENT OF HCC
against placebo for patients who failed or could not tolerate
sorafenib.
Hepatocyte Growth Factor (HGF)/c-Met Inhibitors
Dysregulation of c-Met is seen in HCC, and silencing the
expression of c-Met inhibits HCC growth in HCC cell lines
and tumor models. Tivantinib (ARQ197), a selective, non-
ATP-competitive inhibitor targeting MET tyrosine kinase, is
under early clinical evaluation. In a press release, tivantinib
reportedly met the primary endpoint of improving TTP in a
randomized phase II study comparing tivantinib with placebo
in previously treated patients. Cabozantinib (XL184), a
dual c-Met/VEGFR-2 inhibitor, also demonstrated early evidence
of antitumor activity in a randomized discontinuation
phase II study with a median PFS of 4.2 months.
MEK Inhibitors
HCC is characterized by frequent MEK/ERK activation in
the absence of RAS or RAF mutation. A multicenter, singlearm
study with a two-stage design was conducted using
selumetinib (AZD6244), a specific inhibitor of MEK, in
advanced HCC. 30 The primary endpoint was RR. No radiographic
responses were seen and TTP was only 8 weeks
suggesting minimal single-agent activity despite evidence of
inhibition of ERK phosphorylation.
Author’s Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
Andrew X. Zhu Bristol-Myers
Squibb; Pfizer;
Sanofi
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Other Molecularly Targeted Agents under
Development in HCC
Multiple genetic and epigenetic changes occur during
hepatocarcinogenesis. These pathways include the PI3K/Akt
pathway, insulin growth factor (IGF) and its receptor
(IGFR), as well as the Wnt/beta-catenin pathway. Multiple
agents targeting these key pathways are under early-stage
evaluation in HCC. The major challenge for future development
of these targeted agents is the identification of predictive
markers for specific drugs so that the targeted
population can be enriched.
Conclusion
Management of HCC continues to be challenging, but
potential treatment options are evolving. A multidisciplinary
evaluation will allow physicians to make the best
treatment decisions for patients. As we continue to improve
the outcomes of curative treatment with resection, liver
transplant, and RFA, many new liver-directed regional
therapies are emerging. Sorafenib remains the only approved
agent for advanced HCC, and its role in the adjuvant
setting following resection or RFA, with TACE, or in combination
with other targeted agents or chemotherapy in the
advanced stage is under investigation. Many targeted
agents with novel mechanisms of action are under active
development.
Stock
Ownership Honoraria
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