WOBURN, Massachusetts and
TOKYO, June
11, 2012 /PRNewswire/ --
- Significant improvements in time to progression (TTP) and
overall survival (OS) observed in patients on tivantinib vs. on
placebo whose tumors were MET-high
- Hepatocellular carcinoma (HCC) is the most common primary
liver cancer and on the rise worldwide[1]
- Phase 3 study among previously treated HCC patients with
MET-high tumors is currently being planned with tivantinib
ArQule, Inc. (Nasdaq: ARQL) and Daiichi Sankyo Co., Ltd. (TSE:
4568) announced final results from a randomized,
placebo-controlled, double-blind, phase 2 clinical trial with the
selective MET inhibitor tivantinib
as a single-agent, investigational, second-line treatment in
hepatocellular carcinoma (HCC). The data was presented at the
48th Annual Meeting of the American Society of Clinical Oncology
(ASCO) (abstract number 4006).
The 107 patients in the trial had unresectable HCC and had
disease progression after first-line therapy or were unable to
tolerate the first-line therapy. Patients were randomized to
receive tivantinib at 360 milligrams (mg) twice daily or 240 mg
twice daily or placebo (2:1 tivantinib:placebo). The primary
endpoint was time to progression (TTP) in the intent to treat (ITT)
population. Other study endpoints were disease control rate
(DCR), progression free survival (PFS), overall survival (OS), as
well as safety for the ITT population and pre-defined MET-high or
MET-low cohorts (as defined by immunohistochemistry).
A statistically significant 56 percent improvement as compared
to placebo was seen in TTP in the ITT population (hazard ratio [HR]
= 0.64; 90 percent confidence intervals [CI] = 0.43-0.94; log rank
p-value = 0.04). The median TTP in tivantinib arm was 1.6 months
and 1.4 months in the placebo arm.
In the MET-high cohort, there were statistically significant
improvements in TTP, PFS and OS:
- Median OS in tivantinib arm was 7.2 months and 3.8 months in
the placebo arm (HR = 0.38; 95 percent CI = 0.18-0.81; log rank
p-value = 0.01)
- Median TTP was 2.9 months in the tivantinib arm and 1.5 months
in the placebo arm (HR = 0.43; 95 percent CI = 0.19-0.97; log rank
p-value = 0.03)
- Median PFS was 2.4 months in the tivantinib arm and 1.5 months
in the placebo arm (HR = 0.45; 95 percent CI = 0.21-0.95; log rank
p-value = 0.02).
There was no significant difference in TTP or OS between
tivantinib and placebo in the MET-low cohorts.
Adverse events were reported at similar rates in the treatment
and placebo arms of the trial, except for a higher incidence of
fatigue and hematologic events, including neutropenia and anemia,
in tivantinib-treated patients. The incidence of hematologic events
decreased following dose reduction of tivantinib from 360 mg twice
daily to 240 mg twice daily. Due to increased incidence of
neutropenia in the 360 mg treatment group, the tivantinib dose was
reduced to 240 mg twice daily for all patients.
"Patients living with this disease need more options to slow
progression. The findings from this tivantinib study represent the
first randomized data reported in HCC with an investigational MET
inhibitor, as single-agent therapy in second-line treatment," said
Lorenza Rimassa, Deputy Director,
Medical Oncology Unit, Humanitas Cancer Center, Milan, Italy. "The data suggest that patients
significantly benefited in time to progression and, importantly,
those in a biologically relevant MET-high subgroup had an
additional significant advantage in overall survival."
"Research has shown that MET is a signaling pathway associated
with poor outcomes in many cancers, including liver cancer and
non-small cell lung cancer (NSCLC)," said Glenn Gormley, MD, PhD, Global Head of Research
& Development and Senior Executive Officer, Daiichi Sankyo Co.,
Ltd. "The strong overall survival results among HCC patients
in this trial whose tumors were MET-high reinforce this previous
research that defines MET as a critical pathway in cancer as well
as the activity of tivantinib as a MET inhibitor."
About Hepatocellular Carcinoma
(HCC)
Globally, liver cancer is the sixth most common cancer (749,000
new cases per year), accounting for 7 percent of all cancers, and
is the third cause of cancer related death (692,000 cases per
year).[2]. HCC represents more than 90
percent of primary liver cancers. [3] Chronic
hepatitis B and C are recognized as the major factors worldwide
increasing the risk of HCC, with risk being even greater in the
presence of co-infection with these
viruses.[4] Cirrhosis is also a risk factor
for development of HCC.
About Tivantinib and the MET pathway
Tivantinib is an orally administered, selective inhibitor of
MET, a receptor tyrosine kinase.
In healthy adult cells, MET is present in normal levels to
support natural cellular function, but in cancer cells MET is
inappropriately and continuously activated for unknown reasons.
When abnormally activated, MET plays multiple roles in aspects of
human cancer, including cancer cell growth, survival, angiogenesis,
invasion and metastasis.
Tivantinib is currently in phase 3 development and has not yet
been approved for any indication. Tivantinib has the
potential to be a first-in-class MET inhibitor for the treatment of
non-small cell lung cancer (NSCLC) and is currently being studied
for other indications including liver and colorectal cancers.
About ArQule and Daiichi Sankyo Co.,
Ltd.
In December 2008, ArQule and
Daiichi Sankyo signed a license, co-development and
co-commercialization agreement for tivantinib (ARQ 197) in the
U.S., Europe, South America and the rest of the world,
excluding Japan, China (including Hong Kong), South
Korea and Taiwan.
About ArQule
ArQule is a biotechnology company engaged in the research and
development of next-generation, small-molecule cancer therapeutics.
The Company's targeted, broad-spectrum products and research
programs are focused on key biological processes that are central
to human cancers. ArQule's lead product candidate, in phase 2
and phase 3 clinical development together with development and
commercialization partner, Daiichi Sankyo, Co. Ltd., is tivantinib,
an oral, selective inhibitor of the MET receptor tyrosine kinase.
The Company's pipeline consists of ARQ 621, designed to
inhibit the Eg5 kinesin motor protein, and ARQ 736, designed to
inhibit the RAF kinases. ArQule's current discovery efforts, which
are based on the ArQule Kinase Inhibitor Platform (AKIP™), are
focused on the identification of novel kinase inhibitors that are
potent, selective and do not compete with ATP (adenosine
triphosphate) for binding to the kinase.
About Daiichi Sankyo
The Daiichi Sankyo Group is dedicated to the creation and supply
of innovative pharmaceutical products to address the diversified,
unmet medical needs of patients in both mature and emerging
markets. While maintaining its portfolio of marketed
pharmaceuticals for hypertension, hyperlipidemia, and bacterial
infections, the Group is engaged in the development of treatments
for thrombotic disorders and focused on the discovery of novel
oncology and cardiovascular-metabolic therapies. Furthermore, the
Daiichi Sankyo Group has created a "Hybrid Business Model," which
will respond to market and customer diversity and optimize growth
opportunities across the value chain. For more information, please
visit http://www.daiichisankyo.com.
This press release contains statements regarding the clinical
trials with tivantinib (ARQ 197) by ArQule and its business
partner, Daiichi Sankyo. These statements are based on the
current beliefs and expectations of both companies, and are subject
to risks and uncertainties that could cause actual results to
differ materially. Positive information about pre-clinical
and early stage clinical trial results does not ensure that later
stage or larger scale clinical trials will be successful. For
example, tivantinib may not demonstrate a promising therapeutic
effect; in addition, it may not demonstrate an appropriate safety
profile in current or later stage or larger scale clinical trials
as a result of known or as yet unanticipated side effects. The
results achieved in later stage trials may not be sufficient to
meet applicable regulatory standards or to justify further
development. Problems or delays may arise during clinical trials or
in the course of developing, testing or manufacturing these
compounds that could lead ArQule or its partners to discontinue
development. Even if later stage clinical trials are
successful, unexpected concerns may arise from analysis of data or
from additional data. Obstacles may arise or issues may be
identified in connection with review of clinical data with
regulatory authorities. Regulatory authorities may disagree with
ArQule's view of the data or require additional data or information
or additional studies. In addition, the planned timing of
initiation and completion of clinical trials for tivantinib are
subject to the ability of ArQule, Daiichi Sankyo, and Kyowa Hakko
Kirin, a licensee of tivantinib, to enroll patients, enter into
agreements with clinical trial sites and investigators, and
overcome technical hurdles and other issues related to the conduct
of the trials for which each of them is responsible. There is
a risk that these issues may not be successfully resolved.
Drug development involves a high degree of risk. Only a
small number of research and development programs
result in the commercialization of a product. Positive
pre-clinical data may not be supported in later stages of
development. Furthermore, ArQule may not have the financial
or human resources to successfully pursue drug discovery in the
future. Moreover, with respect to partnered programs, even if
certain compounds show initial promise, Daiichi Sankyo or Kyowa
Hakko Kirin may decide not to license or continue to develop them,
as the case may be. In addition, Daiichi Sankyo and Kyowa
Hakko Kirin have certain rights to unilaterally terminate their
agreements with ArQule. If either company were to do so, ArQule
might not be able to complete development and commercialization of
the applicable licensed products on its own. For more detailed
information on the risks and uncertainties associated with ArQule's
drug development and other activities, see ArQule's periodic
reports filed with the Securities and Exchange Commission. Neither
ArQule nor Daiichi Sankyo undertake any obligation to publicly
update any forward-looking statements.
1. Hepatocellular carcinoma:
Epidemiology, risk factors and pathogenesis. World Journal of
Gastroenterology 14(27): 4300-08, 2008.
2. EASL-EORTC Clinical Practice
Guidelines: Management of hepatocellular carcinoma. Journal of
Hepatology. 2012;56: 908-943
3. EASL-EORTC Clinical Practice
Guidelines: Management of hepatocellular carcinoma. Journal of
Hepatology. 2012;56: 908-943
4. Chiaramonte M, Stroffolini T, Vian
A, et al.: Rate of incidence of hepatocellular carcinoma in
patients with compensated viral cirrhosis. Cancer 85 (10): 2132-37,
1999.
