2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 3. New Agents/Regimens under Development in Advanced
Hepatocellular Carcinoma 25
Agents/Regimen
Phase III, first-line Phase III, second-line
● Sorafenib/erlotinib ● Brivanib (failed)
● Sorafenib/doxorubicin ● Everolimus
● Sunitinib (failed) ● Ramucirumab
● Brivanib ● ADI-PEG 20
● Linifanib
Phase I-II
Single-agent study:
Antiangiogenic agents
● Sunitinib, brivanib, bevacizumab, ramucirumab, TSU-68, linifanib,
cediranib, pazopanib, lenvatinib, lenalidomide, and axitinib
Epidermal growth factor receptor inhibitors
● Erlotinib, gefitinib, lapatinib, cetuximab
mTOR inhibitors
● Everolimus, temsirolimus, and sirolimus
c-Met inhibitors
● Tivantinib (ARQ197), and cabozantinib (XL184)
MEK inhibitors
● Selumetinib (AZD6244)
Histone deacetylase inhibitor
● Belinostat
HSP-90 inhibitor
● STA-9090
Combined targeted agents
● Bevacizumab�erlotinib, sorafenib�everolimas, sorafenib�AZD6244,
sorafenib�bevacizumab, sorafenib� temsirolimus, sorafenib and vorinostat,
sorafenib �GC33, sorafenib� OSI-906
kinases (RTKs) including VEGFR-1, VEGFR-2, PDGFRalpha/beta,
c-KIT, FLT3, and RET kinases. Following the
initial experience of sunitinib from several single-arm phase
II studies that used three different dose schedules, a randomized
phase III study comparing sunitinib at 37.5 mg
continuous daily dosing with sorafenib at 400 mg twice daily
in advanced HCC was conducted. Unfortunately, in this
large study of 1,073 patients, sunitinib failed to demonstrate
either superiority or noninferiority in OS when compared
with sorafenib. 26 Toxicities including thrombocytopenia and
neutropenia were seen with sunitinib leading to discontinuation.
Brivanib alaninate is a dual inhibitor of VEGFR and
fibroblast growth factor receptor (FGFR) signaling pathways
that can induce tumor growth inhibition in mouse HCC
xenograft models. A phase II study was conducted to assess
the efficacy and safety of brivanib in patients with unresectable,
locally advanced, or metastatic HCC who had received
either no prior systemic therapy (Cohort A, 55 patients) or
one prior regimen of angiogenesis inhibitor (Cohort B, 46
patients). Treatment schedule consisted of continuous daily
dosing of brivanib at 800 mg. Both schedules reported
preliminary evidence of antitumor activity. Median
progression-free survival (PFS) and OS were 2.7 (95% CI,
1.4–3.0) and 10 months (95% CI, 6.8–15.2) in the first-line
study. 27 Median OS and time to progression (TTP) as assessed
by study investigators following second-line treatment
with brivanib were 9.79 and 2.7 months,
respectively. 28 Despite the ambitious phase III development
program with brivanib in HCC, a recent press release
reported that brivanib failed to demonstrate improved OS
when compared with placebo in patients with advanced
HCC who failed sorafenib. Linifanib (ABT-869) is a potent
and selective inhibitor of VEGFR and PDGFR. Preliminary
278
results from an open label, multicenter phase II study of
linifanib in advanced HCC were reported. Linifanib was
given at 0.25 mg/kg daily in Child-Pugh A. For all 34
patients, median TTP was 112 days and median OS was
295 days (95% CI, 182–333). A phase III study comparing
linifanib with sorafenib should complete in the near future.
Ramucirumab (IMC-1121B), a recombinant human monoclonal
antibody against VEGFR-2, has been examined in a
phase II study. This demonstrated a response rate (RR) of
10%, PFS of 4.0 months, and OS of 12.0 months in patients
who have not received prior systemic therapy. Remucirumab
is undergoing phase III development in the secondline
setting against placebo in patients where sorafenib
failed.
Several other antiagiogenic agents are at early stages of
clinical development in HCC. These include bevacizumab, 29
cediranib, pazopanib, lenvatinib, and axitinib. The abundance
of VEGF inhibitors that entered HCC clinical trials
and the failure of sunitinib and brivanib in phase III trials
have prompted us to reconsider the relevance of targeting
VEGF receptors in HCC. The challenge of developing additional
antiangiogenic agents in HCC is to understand the
mechanisms of action and develop potential surrogate and
predictive markers to identify patients likely to benefit from
treatment. Although we aim to select the most potent
inhibitors, the safety profiles of these agents including
bleeding, thromboembolic events, skin rashes, and hypertension
should be carefully evaluated.
Epidermal Growth Factor Receptor (EGFR) Inhibitors
Increasing evidence has highlighted the importance of
EGFR/HER1 and its ligands EGF and transforming growth
factor-alpha (TGF-alpha) in hepatocarcinogenesis. The expression
of several EGF family members, specifically EGF,
TGF-alpha, and heparin-binding–epidermal growth factor,
as well as EGFR, has been described in several HCC cell
lines and tissues. Multiple strategies to target EGFR signaling
pathways have been developed, and two classes of
anti-EGFR agents are tested in HCC: monoclonal antibodies
that competitively inhibit extracellular endogenous ligand
binding and small molecules that inhibit the intracellular
tyrosine kinase (TK) domain. With the exception of erlotinib
showing modest activity in single-arm studies, the other
EGFR inhibitors (gefinitib, lapatinib, and cetuximab) have
not demonstrated convincing antitumor activity as single
agents. Only erlotinib is being examined in an ongoing
phase III study in combination with sorafenib.
mTOR Inhibitors
ANDREW X. ZHU
Mammalian target of rapamycin (mTOR) functions to
regulate protein translation, angiogenesis, and cell cycle
progression in many cancers including HCC. Preclinical
data have demonstrated that mTOR inhibitors were effective
in inhibiting cell growth and tumor vascularity in HCC
cell lines and HCC tumor models. Aberrant mTOR signaling
was present in half of the HCC cases and correlated with
HCC recurrence following resection.
A number of mTOR inhibitors (sirolimus, temsirolimus,
and everolimus) are under clinical development in HCC.
Early evidence of tolerability and efficacy has emerged from
phase I and II studies with everolimus, which has led to the
ongoing randomized phase III study comparing everolimus