– Trial results formed the basis of regulatory filings in the U.S.
and European Union for CABOMETYX®
(cabozantinib) for previously treated advanced hepatocellular carcinoma –
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Jul. 4, 2018--
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
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.
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
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
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,
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
Exelixis, the Exelixis logo, CABOMETYX, COMETRIQ and COTELLIC are
registered U.S. trademarks.
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
Accessed July 2018.
3American 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.
View source version on businesswire.com: https://www.businesswire.com/news/home/20180704005004/en/
Source: Exelixis, Inc.
EVP, Public Affairs and Investor Relations
Lindsay Treadway, 650-837-7522
Director, Public Affairs and Advocacy Relations