– In the pivotal phase 3 CELESTIAL trial, CABOMETYX provided a
statistically significant and clinically meaningful improvement versus
placebo in overall survival (OS) –
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Mar. 15, 2018--
Inc. (NASDAQ:EXEL) today announced it has completed the submission
of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug
Administration (FDA) for CABOMETYX® (cabozantinib) tablets as a
treatment for patients with previously treated advanced hepatocellular
carcinoma (HCC). The sNDA submission is based on results from the
CELESTIAL randomized pivotal phase 3 trial of CABOMETYX in patients with
advanced HCC who received prior sorafenib.
“We look forward to working closely with regulatory authorities through
the review process in anticipation of bringing CABOMETYX to people
diagnosed with advanced hepatocellular carcinoma, an underserved patient
community that urgently needs new treatment options,” said Gisela
Schwab, M.D., President, Product Development and Medical Affairs and
Chief Medical Officer, Exelixis. "We would sincerely like to thank the
study patients and clinicians who participated in the CELESTIAL trial as
well as our dedicated clinical development, medical and regulatory teams
for bringing us another step closer to our goal of fully exploring the
potential of CABOMETYX and making it accessible to every patient who may
benefit from its use.”
On October 16, 2017, Exelixis announced that the independent data
monitoring committee for the study recommended that the CELESTIAL 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 (pre-specified critical
p-value ≤ 0.021). In March 2017, the FDA granted orphan drug designation
to cabozantinib for the treatment of advanced HCC.
An sNDA is an application to the FDA that, if approved, will allow a
drug sponsor to make changes to a previously approved product label,
including modifications to the indication.
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
progression-free survival. Exploratory endpoints include
patient-reported outcomes, biomarkers and safety.
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.1 In the U.S., the incidence of
liver cancer has more than tripled since 1980.2 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 2018.2 HCC
is the fastest-rising cause of cancer-related death in U.S.3
Without treatment, patients with advanced HCC usually survive less than
About CABOMETYX® (cabozantinib)
tablets are approved in the United States for the treatment of patients
with advanced 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 vascular
endothelial growth factor (VEGF)-targeted therapy. Ipsen also submitted
to European Medicines Agency (EMA) the regulatory dossier for
cabozantinib as a treatment for first-line advanced RCC in the European
Union on August 28, 2017; on September 8, 2017, Ipsen announced that the
EMA validated the application. 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 https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
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 lead compounds, cabozantinib and
cobimetinib, and advanced them into clinical development before entering
into partnerships with leading biopharmaceutical companies in our
efforts to bring these medicines to patients globally. We are steadfast
in our commitment to prudently reinvest in our business to maximize the
potential of our pipeline. We intend to supplement 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. Exelixis
recently earned a spot on Deloitte’s Technology Fast 500 list, a yearly
award program honoring the 500 fastest-growing companies over the past
four years. 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
release contains forward-looking statements, including, without
limitation, statements related to: the regulatory review process;
Exelixis’ goal of expanding the population of patients who might benefit
from CABOMETYX and the potential to bring CABOMETYX to patients
diagnosed with advanced HCC; the therapeutic potential of CABOMETYX as a
treatment for patients with 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 “look forward,” “anticipation,” “goal,” “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;
risks related to the potential failure of cabozantinib to demonstrate
safety and efficacy in clinical testing; Exelixis’ ability and the
ability of its collaborators to conduct clinical trials of cabozantinib,
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
cabozantinib and cobimetinib in the territories where they are approved;
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; 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; changes in economic and business conditions, and other
factors discussed under the caption “Risk Factors” in Exelixis’ annual
report on Form 10-K filed with the Securities and Exchange Commission
(SEC) on February 26, 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 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 March 2018.
2American 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 March 2018.
3 Mittal S, El-Serag HB.
Epidemiology of HCC: Consider the Population. Journal of Clinical
Gastroenterology. 2013. 47:S2-S6.
4 Weledji E, Orock
G, Ngowe M, NsaghaD. How grim is hepatocellular carcinoma? Annals of
Medicine and Surgery. 2014. 3:71-76.
View source version on businesswire.com: http://www.businesswire.com/news/home/20180315005365/en/
Source: Exelixis, Inc.
EVP, Public Affairs and Investor
Senior Director, Public Affairs and