– Approval based on statistically
significant and clinically meaningful overall survival benefit
demonstrated in the CELESTIAL phase 3 pivotal trial –
– Exelixis prepared to fully support new
indication immediately –
Exelixis, Inc. (NASDAQ:EXEL) today announced that the U.S. Food
and Drug Administration (FDA) approved CABOMETYX® (cabozantinib)
tablets for patients with hepatocellular carcinoma (HCC) who have
been previously treated with sorafenib. HCC is the most common form
of liver cancer and the fastest-rising cause of cancer-related
death in the U.S.1
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CABOMETYX® Tablets 60 mg, 40 mg, 20 mg
(Photo: Business Wire)
“This new indication for CABOMETYX is an important treatment
advance for patients with this aggressive form of liver cancer, a
community in need of new therapeutic options,” said Michael M.
Morrissey, Ph.D., President and Chief Executive Officer of
Exelixis. “This approval is an important milestone as we continue
to explore how CABOMETYX may benefit people with
difficult-to-treat-cancers beyond renal cell carcinoma. We would
like to thank the patients and clinicians who participated in
CELESTIAL and to acknowledge the team at the FDA for their
continued collaboration during the review of our application.”
The FDA’s approval of CABOMETYX was based on results from the
CELESTIAL phase 3 pivotal trial of CABOMETYX for patients with
advanced HCC who received prior sorafenib. CABOMETYX demonstrated a
statistically significant and clinically meaningful improvement in
overall survival (OS) versus placebo. On November 15, 2018,
Exelixis’ partner Ipsen received approval from the European
Commission for CABOMETYX tablets as a monotherapy for HCC in adults
who have previously been treated with sorafenib.
“Patients with this form of advanced liver cancer have few
treatment options, particularly 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. “Physicians are eager for new options
for these patients, and the results of the CELESTIAL trial
demonstrate that CABOMETYX has the efficacy and safety profile to
become an important new therapy in our efforts to slow disease
progression and improve treatment outcomes.”
In the pivotal CELESTIAL trial, median OS 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.
Adverse events in CELESTIAL 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.
“While we’ve seen some progress in the treatment of primary
liver cancer in recent years, the patient community still needs new
and better options,” said Andrea Wilson, President and Founder of
Blue Faery: The Adrienne Wilson Liver Cancer Association. “The
approval of CABOMETYX has been eagerly anticipated, making this an
important day for patients diagnosed with this devastating
disease.”
In December 2018, Exelixis and its partner Ipsen announced the
initiation of COSMIC-312, a phase 3 pivotal trial of cabozantinib
in combination with atezolizumab versus sorafenib in previously
untreated advanced HCC. The trial will also explore single-agent
activity of cabozantinib in the first-line setting. For more
information about the trial, visit ClinicalTrials.gov.
Please see Important Safety Information below and full U.S.
prescribing information at
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
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. The data, originally presented at the 2018 American
Society of Clinical Oncology’s Gastrointestinal Cancers Symposium
(ASCO-GI) in January 2018, were published in The New England
Journal of Medicine in July 2018.2
About HCC
Liver cancer is a leading cause of cancer death worldwide,
accounting for more than 700,000 deaths and 800,000 new cases each
year.3 In the U.S., the incidence of liver cancer has more than
tripled since 1980.4 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 2019.4 HCC is the fastest-rising cause of
cancer-related death in the U.S.1 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) and
for the treatment of patients with HCC who have been previously
treated with sorafenib. CABOMETYX tablets are also approved in: the
European Union, Norway, Iceland, Australia, Switzerland, South
Korea, Hong Kong, Ukraine, Canada, Taiwan, Jordan, and Macau for
the treatment of advanced RCC in adults who have received prior
VEGF-targeted therapy; in the European Union, Norway, Iceland,
Australia, and Jordan for previously untreated intermediate- or
poor-risk advanced RCC; in Canada for adult patients with advanced
RCC who have received prior VEGF targeted therapy; in advanced or
metastatic RCC in Brazil; and in the European Union, Norway and
Iceland for HCC in adults who have previously been treated with
sorafenib. 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.
U.S. Important Safety Information
- Hemorrhage: Severe and fatal
hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5
hemorrhagic events was 5% in CABOMETYX patients. Discontinue
CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX
to patients who have a recent history of hemorrhage, including
hemoptysis, hematemesis, or melena.
- Perforations and Fistulas:
GastrointestinaI (GI) perforations, including fatal cases, occurred
in 1% of CABOMETYX patients. Fistulas, including fatal cases,
occurred in 1% of CABOMETYX patients. Monitor patients for signs
and symptoms of perforations and fistulas, including abscess and
sepsis. Discontinue CABOMETYX in patients who experience a fistula
that cannot be appropriately managed or a GI perforation.
- Thrombotic Events: CABOMETYX
increased the risk of thrombotic events. Venous thromboembolism
occurred in 7% (including 4% pulmonary embolism) and arterial
thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic
events occurred in CABOMETYX patients. Discontinue CABOMETYX in
patients who develop an acute myocardial infarction or serious
arterial or venous thromboembolic event requiring medical
intervention.
- Hypertension and Hypertensive
Crisis: CABOMETYX can cause hypertension, including
hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and
<1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in
patients with uncontrolled hypertension. Monitor blood pressure
regularly during CABOMETYX treatment. Withhold CABOMETYX for
hypertension that is not adequately controlled with medical
management; when controlled, resume at a reduced dose. Discontinue
CABOMETYX for severe hypertension that cannot be controlled with
anti-hypertensive therapy or for hypertensive crisis.
- Diarrhea: Diarrhea occurred in
63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of
CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1
and resume at a reduced dose for intolerable Grade 2 diarrhea,
Grade 3 diarrhea that cannot be managed with standard antidiarrheal
treatments, or Grade 4 diarrhea.
- Palmar-Plantar Erythrodysesthesia
(PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE
occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until
improvement to Grade 1 and resume at a reduced dose for intolerable
Grade 2 PPE or Grade 3 PPE.
- Proteinuria: Proteinuria
occurred in 7% of CABOMETYX patients. Monitor urine protein
regularly during CABOMETYX treatment. Discontinue CABOMETYX in
patients who develop nephrotic syndrome.
- Osteonecrosis of the Jaw (ONJ):
ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as
jaw pain, osteomyelitis, osteitis, bone erosion, tooth or
periodontal infection, toothache, gingival ulceration or erosion,
persistent jaw pain, or slow healing of the mouth or jaw after
dental surgery. Perform an oral examination prior to CABOMETYX
initiation and periodically during treatment. Advise patients
regarding good oral hygiene practices. Withhold CABOMETYX for at
least 28 days prior to scheduled dental surgery or invasive dental
procedures. Withhold CABOMETYX for development of ONJ until
complete resolution.
- Wound Complications: Wound
complications were reported with CABOMETYX. Stop CABOMETYX at least
28 days prior to scheduled surgery. Resume CABOMETYX after surgery
based on clinical judgment of adequate wound healing. Withhold
CABOMETYX in patients with dehiscence or wound healing
complications requiring medical intervention.
- Reversible Posterior
Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of
subcortical vasogenic edema diagnosed by characteristic finding on
MRI, can occur with CABOMETYX. Evaluate for RPLS in patients
presenting with seizures, headache, visual disturbances, confusion,
or altered mental function. Discontinue CABOMETYX in patients who
develop RPLS.
- Embryo-Fetal Toxicity: CABOMETYX
can cause fetal harm. Advise pregnant women and females of
reproductive potential of the potential risk to a fetus. Verify the
pregnancy status of females of reproductive potential prior to
initiating CABOMETYX and advise them to use effective contraception
during treatment and for 4 months after the last dose.
- Adverse Reactions: The most
commonly reported (≥25%) adverse reactions are: diarrhea, fatigue,
decreased appetite, PPE, nausea, hypertension, and vomiting.
- Strong CYP3A4 Inhibitors: If
coadministration with strong CYP3A4 inhibitors cannot be avoided,
reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit
juice.
- Strong CYP3A4 Inducers: If
coadministration with strong CYP3A4 inducers cannot be avoided,
increase the CABOMETYX dosage. Avoid St. John’s wort.
- Lactation: Advise women not to
breastfeed during CABOMETYX treatment and for 4 months after the
final dose.
- Hepatic Impairment: In patients
with 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.
Exelixis is a member of 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 Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: Exelixis’
preparedness to fully support the indication of previously treated
advanced HCC immediately; Exelixis’ plans to continue to explore
how CABOMETYX may benefit people with difficult-to-treat cancers
beyond RCC; the potential for CABOMETYX to become an important new
therapy that slows disease progression and improves treatment
outcomes for patients with HCC who have progressed following
treatment with sorafenib; and 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. Any statements that refer to expectations,
projections or other characterizations of future events or
circumstances are forward-looking statements and 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: the degree of market acceptance of
CABOMETYX and the availability of sufficient coverage and adequate
reimbursement for this product; the strength of CABOMETYX sales
efforts, marketing, medical affairs and distribution support; the
effectiveness of CABOMETYX in comparison to competing products;
uncertainties inherent in the product development process; the
level of costs associated with Exelixis’ cabozantinib development
activities; Exelixis’ continuing compliance with applicable legal
and regulatory requirements; Exelixis’ ability to protect its
intellectual property rights; Exelixis’ dependence on third-party
vendors for the manufacture and supply of cabozantinib; market
competition, including the potential for competitors to obtain
approval for generic versions of CABOMETYX; changes in economic and
business conditions; and other factors affecting Exelixis’ ability
to commercialize CABOMETYX and expand the cabozantinib development
program discussed under the caption “Risk Factors” in Exelixis’
Quarterly Report on Form 10-Q filed with the Securities and
Exchange Commission (SEC) on November 1, 2018, and in Exelixis’
future filings with the SEC. All forward-looking statements in this
press release are based on information available to Exelixis as of
the date of this press release, and Exelixis undertakes no
obligation to update or revise any forward-looking statements
contained herein.
Exelixis, the Exelixis logo, CABOMETYX,
COMETRIQ and COTELLIC are registered U.S. trademarks.
# # #
1 Mittal S, El-Serag HB. Epidemiology of HCC: Consider the
Population. J Clin Gastroenterol. 2013. 47:S2-S6. 2 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. 3
International Agency for Research on
Cancer. GLOBOCAN 2018. Liver Fact Sheet. Available at:
http://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf.
Accessed January 2019.
4
American Cancer Society: Cancer Facts and
Figures 2019. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf.
Accessed January 2019.
5 Weledji E, Orock G, Ngowe M, NsaghaD. How grim is hepatocellular
carcinoma? Ann Med Surg. 2014. 3:71-76.
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version on businesswire.com: https://www.businesswire.com/news/home/20190114005830/en/
Investors:Susan HubbardEVP, Public Affairs and Investor
RelationsExelixis, Inc.(650) 837-8194shubbard@exelixis.com
Media:Lindsay TreadwaySenior Director, Public Affairs and
Advocacy RelationsExelixis, Inc.(650)
837-7522ltreadway@exelixis.com
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