– Trial results formed the basis of
regulatory filings in the U.S. and European Union for
CABOMETYX® (cabozantinib) for previously treated
advanced hepatocellular carcinoma –
Exelixis, Inc. (Nasdaq: EXEL) today announced that The New
England Journal of Medicine (NEJM) published results from the
CELESTIAL phase 3 pivotal trial of cabozantinib in patients with
previously treated advanced hepatocellular carcinoma (HCC).1 The
data, originally presented at the 2018 American Society of Clinical
Oncology’s Gastrointestinal Cancers Symposium (ASCO-GI) in January,
demonstrate that cabozantinib provided a statistically significant
and clinically meaningful improvement in overall survival (OS)
versus placebo.
“Patients with this form of advanced liver cancer have very
limited treatment options once their disease progresses following
treatment with sorafenib,” said Ghassan K. Abou-Alfa, M.D.,
Memorial Sloan Kettering Cancer Center, New York and lead
investigator on CELESTIAL. “These results suggest that, if
approved, cabozantinib could become an important addition to the
treatment landscape that may help slow disease progression and,
critically, improve survival for these patients.”
Exelixis announced in May 2018 that the U.S. Food and Drug
Administration (FDA) accepted the company’s supplemental New Drug
Application (sNDA) for CABOMETYX® (cabozantinib) tablets as a
treatment for patients with previously treated HCC. The filing has
been assigned a Prescription Drug User Fee Act action date of
January 14, 2019. Exelixis’ partner Ipsen received validation by
the European Medicines Agency in March 2018 for its application for
variation to the CABOMETYX marketing authorization to include the
new indication for patients with previously treated advanced
HCC.
“The publication of the CELESTIAL trial results in a
peer-reviewed publication as prestigious as NEJM further validates
the importance of these data for the advanced liver cancer
community,” said Gisela Schwab, M.D., President, Product
Development and Medical Affairs and Chief Medical Officer,
Exelixis. “We’re working closely with the FDA as they review our
sNDA in order to bring CABOMETYX to this growing patient population
as quickly as possible.”
Median OS in CELESTIAL was 10.2 months with cabozantinib versus
8.0 months with placebo (HR 0.76, 95 percent CI 0.63-0.92;
p=0.0049). Median progression-free survival (PFS) was more than
doubled, at 5.2 months with cabozantinib and 1.9 months with
placebo (HR 0.44, 95 percent CI 0.36-0.52; p<0.0001). Objective
response rates per RECIST 1.1 were 4 percent with cabozantinib and
0.4 percent with placebo (p=0.0086). Disease control (partial
response or stable disease) was achieved by 64 percent of patients
in the cabozantinib group compared with 33 percent of patients in
the placebo group.
In a subgroup analysis of patients whose only prior therapy for
advanced HCC was sorafenib (70 percent of patients in the study),
median OS was 11.3 months with cabozantinib versus 7.2 months with
placebo (HR 0.70, 95 percent CI 0.55-0.88). Median PFS in the
subgroup was 5.5 months with cabozantinib versus 1.9 months with
placebo (HR 0.40, 95 percent CI 0.32-0.50).
Adverse events were consistent with the known safety profile of
cabozantinib. The most common (≥10 percent) grade 3 or 4 adverse
events in the cabozantinib group compared to the placebo group were
palmar-plantar erythrodysesthesia (17 percent vs. 0 percent),
hypertension (16 percent vs. 2 percent), increased aspartate
aminotransferase (12 percent vs. 7 percent), fatigue (10 percent
vs. 4 percent) and diarrhea (10 percent vs. 2 percent).
Treatment-related grade 5 adverse events occurred in six patients
in the cabozantinib group (hepatic failure, esophagobronchial
fistula, portal vein thrombosis, upper gastrointestinal hemorrhage,
pulmonary embolism and hepatorenal syndrome) and in one patient in
the placebo group (hepatic failure). Sixteen percent of patients in
the cabozantinib arm and three percent of patients in the placebo
arm discontinued treatment due to treatment-related adverse
events.
About the CELESTIAL Study
CELESTIAL is a randomized, double-blind, placebo-controlled
study of cabozantinib in patients with advanced HCC conducted at
more than 100 sites globally in 19 countries. The trial was
designed to enroll 760 patients with advanced HCC who received
prior sorafenib and may have received up to two prior systemic
cancer therapies for HCC and had adequate liver function.
Enrollment of the trial was completed in September 2017. Patients
were randomized 2:1 to receive 60 mg of cabozantinib once daily or
placebo and were stratified based on etiology of the disease
(hepatitis C, hepatitis B or other), geographic region (Asia versus
other regions) and presence of extrahepatic spread and/or
macrovascular invasion (yes or no). No cross-over was allowed
between the study arms during the blinded treatment phase of the
trial. The primary endpoint for the trial is OS, and secondary
endpoints include objective response rate and PFS. Exploratory
endpoints include patient-reported outcomes, biomarkers and
safety.
In October 2017, Exelixis announced that the independent data
monitoring committee for the CELESTIAL study recommended that the
trial be stopped for efficacy following review at the second
planned interim analysis, with cabozantinib providing a
statistically significant and clinically meaningful improvement in
OS compared with placebo in patients with previously treated
advanced HCC. In March 2017, the FDA granted orphan drug
designation to cabozantinib for the treatment of advanced HCC.
About HCC
Liver cancer is the second-leading cause of cancer death
worldwide, accounting for more than 700,000 deaths and nearly
800,000 new cases each year.2 In the U.S., the incidence of liver
cancer has more than tripled since 1980.3 HCC is the most common
form of liver cancer, making up about three-fourths of the
estimated nearly 42,000 new cases in the U.S. in 2018.3 HCC is the
fastest-rising cause of cancer-related death in U.S.4 Without
treatment, patients with advanced HCC usually survive less than 6
months.5
About CABOMETYX® (cabozantinib)
CABOMETYX tablets are approved in the United States for the
treatment of patients with advanced renal cell carcinoma (RCC).
CABOMETYX tablets are also approved in the European Union, Norway,
Iceland, Australia, Switzerland and South Korea for the treatment
of advanced RCC in adults who have received prior VEGF-targeted
therapy, and in the European Union for previously untreated
intermediate- or poor-risk advanced RCC. On March 28, 2018, Ipsen
announced that the European Medicines Agency validated its
application for a new indication for cabozantinib as a treatment
for previously treated advanced HCC in the European Union. In 2016,
Exelixis granted Ipsen exclusive rights for the commercialization
and further clinical development of cabozantinib outside of the
United States and Japan. In 2017, Exelixis granted exclusive rights
to Takeda Pharmaceutical Company Limited for the commercialization
and further clinical development of cabozantinib for all future
indications in Japan, including RCC.
CABOMETYX is not indicated for previously treated advanced
HCC.
Please see Important Safety Information below and full U.S.
prescribing information at
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
U.S. Important Safety Information
- Hemorrhage: Severe and fatal
hemorrhages have occurred with CABOMETYX. In two RCC studies, the
incidence of Grade ≥ 3 hemorrhagic events was 3% in
CABOMETYX-treated patients. Do not administer CABOMETYX to patients
that have or are at risk for severe hemorrhage.
- Gastrointestinal (GI) Perforations
and Fistulas: In RCC studies, fistulas were reported in 1% of
CABOMETYX-treated patients. Fatal perforations occurred in patients
treated with CABOMETYX. In RCC studies, gastrointestinal (GI)
perforations were reported in 1% of CABOMETYX-treated patients.
Monitor patients for symptoms of fistulas and perforations,
including abscess and sepsis. Discontinue CABOMETYX in patients who
experience a fistula which cannot be appropriately managed or a GI
perforation.
- Thrombotic Events: CABOMETYX
treatment results in an increased incidence of thrombotic events.
In RCC studies, venous thromboembolism occurred in 9% (including 5%
pulmonary embolism) and arterial thromboembolism occurred in 1% of
CABOMETYX-treated patients. Fatal thrombotic events occurred in the
cabozantinib clinical program. Discontinue CABOMETYX in patients
who develop an acute myocardial infarction or any other arterial
thromboembolic complication.
- Hypertension and Hypertensive
Crisis: CABOMETYX treatment results in an increased incidence
of treatment-emergent hypertension, including hypertensive crisis.
In RCC studies, hypertension was reported in 44% (18% Grade
≥ 3) of CABOMETYX-treated patients. Monitor blood pressure
prior to initiation and regularly during CABOMETYX treatment.
Withhold CABOMETYX for hypertension that is not adequately
controlled with medical management; when controlled, resume
CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe
hypertension that cannot be controlled with anti-hypertensive
therapy. Discontinue CABOMETYX if there is evidence of hypertensive
crisis or severe hypertension despite optimal medical
management.
- Diarrhea: In RCC studies,
diarrhea occurred in 74% of patients treated with CABOMETYX.
Grade 3 diarrhea occurred in 11% of patients treated with
CABOMETYX. Withhold CABOMETYX in patients who develop intolerable
Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with
standard antidiarrheal treatments until improvement to Grade 1;
resume CABOMETYX at a reduced dose.
- Palmar-Plantar Erythrodysesthesia
(PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE)
occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE
occurred in 8% of patients treated with CABOMETYX. Withhold
CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade
3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced
dose.
- Reversible Posterior
Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical
vasogenic edema diagnosed by characteristic finding on MRI,
occurred in the cabozantinib clinical program. Perform an
evaluation for RPLS in any patient presenting with seizures,
headache, visual disturbances, confusion or altered mental
function. Discontinue CABOMETYX in patients who develop RPLS.
- Embryo-fetal Toxicity may be
associated with CABOMETYX. Advise pregnant women of the potential
risk to a fetus. Advise females of reproductive potential to use
effective contraception during CABOMETYX treatment and for 4 months
after the last dose.
- Adverse Reactions: The most
commonly reported (≥25%) adverse reactions are: diarrhea, fatigue,
nausea, decreased appetite, hypertension, PPE, weight decreased,
vomiting, dysgeusia, and stomatitis.
- Strong CYP3A4 Inhibitors: If
concomitant use with strong CYP3A4 inhibitors cannot be avoided,
reduce the CABOMETYX dosage.
- Strong CYP3A4 Inducers: If
concomitant use with strong CYP3A4 inducers cannot be avoided,
increase the CABOMETYX dosage.
- Lactation: Advise women not to
breastfeed while taking CABOMETYX and for 4 months after the final
dose.
- Hepatic Impairment: In patients
with mild to moderate hepatic impairment, reduce the CABOMETYX
dosage. CABOMETYX is not recommended for use in patients with
severe hepatic impairment.
Please see accompanying full Prescribing Information
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About Exelixis
Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially
successful, oncology-focused biotechnology company that strives to
accelerate the discovery, development and commercialization of new
medicines for difficult-to-treat cancers. Following early work in
model genetic systems, we established a broad drug discovery and
development platform that has served as the foundation for our
continued efforts to bring new cancer therapies to patients in
need. We discovered our three commercially available products,
CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib) and COTELLIC®
(cobimetinib), and have entered into partnerships with leading
pharmaceutical companies to bring these important medicines to
patients worldwide. Supported by revenues from our marketed
products and collaborations, we are committed to prudently
reinvesting in our business to maximize the potential of our
pipeline. We are supplementing our existing therapeutic assets with
targeted business development activities and internal drug
discovery – all to deliver the next generation of Exelixis
medicines and help patients recover stronger and live longer. In
July 2018, Exelixis was added to the Standard & Poor’s
(S&P) MidCap 400 index, which measures the performance of
profitable mid-sized companies. For more information about
Exelixis, please visit www.exelixis.com, follow @ExelixisInc on
Twitter or like Exelixis, Inc. on Facebook.
Exelixis Forward-Looking Statement Disclaimer
This press release contains forward-looking statements,
including, without limitation, statements related to: the
therapeutic potential of cabozantinib as a treatment option for
patients with previously treaded advanced HCC, if approved; the
regulatory review process, including Exelixis’ intent to continue
to work closely with the FDA as they review the application for
cabozantinib as a treatment for patients with previously treated
advanced HCC; Exelixis’ plans to reinvest in its business to
maximize the potential of the company’s pipeline, including through
targeted business development activities and internal drug
discovery; and Exelixis’ mission to deliver the next generation of
Exelixis medicines and help patients recover stronger and live
longer. Words such as “could” “may,” “commitment,” “potential,”
“intend,” or other similar expressions identify forward-looking
statements, but the absence of these words does not necessarily
mean that a statement is not forward-looking. In addition, any
statements that refer to expectations, projections or other
characterizations of future events or circumstances are
forward-looking statements. These forward-looking statements are
based upon Exelixis’ current plans, assumptions, beliefs,
expectations, estimates and projections. Forward-looking statements
involve risks and uncertainties. Actual results and the timing of
events could differ materially from those anticipated in the
forward-looking statements as a result of these risks and
uncertainties, which include, without limitation: risks and
uncertainties related to regulatory review and approval processes
and Exelixis’ compliance with applicable legal and regulatory
requirements; market acceptance of CABOMETYX, COMETRIQ, and
COTELLIC and the availability of coverage and reimbursement for
these products; the risk that unanticipated developments could
adversely affect the commercialization of CABOMETYX, COMETRIQ, and
COTELLIC; risks related to the potential failure of cabozantinib
and cobimetinib to demonstrate safety and efficacy in clinical
testing; Exelixis’ ability and the ability of its collaborators to
conduct clinical trials of cabozantinib and cobimetinib, both alone
and in combination with other therapies, sufficient to achieve a
positive completion; Exelixis’ dependence on its relationships with
its collaboration partners, including, the level of their
investment in the resources necessary to successfully commercialize
partnered products in the territories where they are approved; the
level of costs associated with Exelixis’ commercialization,
research and development, in-licensing or acquisition of product
candidates, and other activities; Exelixis’ dependence on
third-party vendors for the development, manufacture and supply of
its products; Exelixis’ ability to protect the company’s
intellectual property rights; market competition, including the
potential for competitors to obtain approval for generic versions
of Exelixis’ marketed products; changes in economic and business
conditions, and other factors discussed under the caption “Risk
Factors” in Exelixis’ annual report on Form 10-Q filed with the
Securities and Exchange Commission (SEC) on May 2, 2018, and in
Exelixis’ future filings with the SEC. The forward-looking
statements made in this press release speak only as of the date of
this press release. Exelixis expressly disclaims any duty,
obligation or undertaking to release publicly any updates or
revisions to any forward-looking statements contained herein to
reflect any change in Exelixis’ expectations with regard thereto or
any change in events, conditions or circumstances on which any such
statements are based.
Exelixis, the Exelixis logo, CABOMETYX,
COMETRIQ and COTELLIC are registered U.S. trademarks.
References:
1 Abou-Alfa, G, Meyer T, Cheng AL, et al. Cabozantinib in
patients with advanced and progressing hepatocellular carcinoma. N
Engl J Med. 2018. 379:54-63.
2 Cancer Incidence and Mortality Worldwide. Liver Cancer.
International Agency for Research on Cancer, GLOBOCAN 2012.
Available at:
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed
July 2018.
3 American Cancer Society: Cancer Facts and Figures 2018.
Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf.
Accessed July 2018.
4 Mittal S, El-Serag HB. Epidemiology of HCC: Consider the
Population. J Clin Gastroenterol. 2013. 47:S2-S6.
5 Weledji E, Orock G, Ngowe M, NsaghaD. How grim is
hepatocellular carcinoma? Ann Med Surg. 2014. 3:71-76.
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Investors:Exelixis, Inc.Susan Hubbard, 650-837-8194EVP,
Public Affairs and Investor
Relationsshubbard@exelixis.comorMedia:Exelixis, Inc.Lindsay
Treadway, 650-837-7522Senior Director, Public Affairs and Advocacy
Relationsltreadway@exelixis.com
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