– Cabozantinib improved overall survival and
progression-free survival irrespective of duration of prior
sorafenib treatment or age category –
Exelixis, Inc. (Nasdaq: EXEL) today announced results from
sub-group analyses of the CELESTIAL phase 3 pivotal trial of
cabozantinib in advanced hepatocellular carcinoma (HCC) comparing
outcomes by duration of sorafenib treatment in patients whose only
prior treatment was sorafenib and outcomes based on age. The
findings, presented in two posters at the American Society of
Clinical Oncology (ASCO) 2018 Annual Meeting during the
Gastrointestinal (Noncolorectal) Cancer Poster Session from 8:00 –
11:00 a.m. CDT in Hall A, showed that cabozantinib improved overall
survival (OS) and progression-free survival (PFS) compared with
placebo irrespective of duration of prior sorafenib treatment or
age category.
“We’re pleased with the encouraging CELESTIAL subgroup data
presented at ASCO, which showed that cabozantinib provided benefits
to patients regardless of duration of prior sorafenib treatment or
age,” said Gisela Schwab, M.D., President, Product Development and
Medical Affairs and Chief Medical Officer, Exelixis. “We continue
to work closely with the U.S. FDA as they review the filing
application for cabozantinib for previously treated advanced
hepatocellular carcinoma and hope it may soon provide a new option
for patients with this difficult-to-treat cancer who have few
alternatives.”
Outcomes in Patients who had Received Sorafenib [abstract
4088]
The sub-analysis of patients in CELESTIAL who received sorafenib
as their only prior systemic therapy was presented by Robin Kate
Kelley, M.D., University of California San Francisco. In this
subgroup-analysis, patients were grouped by the length of time they
had been treated with sorafenib (less than three months; three to
six months; more than six months) to assess the effect of
cabozantinib in patients with varying benefit from prior sorafenib.
In all three groups, cabozantinib improved OS and PFS versus
placebo:
Duration
of Prior Sorafenib* <3 Months
3 to <6 Months ≥6
Months
Cabozantinib(n=89)
Placebo(n=47)
Cabozantinib(n=98)
Placebo(n=43)
Cabozantinib(n=143)
Placebo(n=74)
Median OS (months) 8.9
6.9 11.5 6.5 12.3
9.2 HR 0.72, 95 percentCI 0.47–1.10
HR 0.65, 95 percentCI 0.43–1.00 HR
0.82, 95 percentCI 0.58–1.16
Median PFS (months)
3.8 1.8 5.4
1.9 5.7 1.9 HR
0.35, 95 percentCI 0.23–0.52 HR 0.37, 95 percentCI
0.25–0.56 HR 0.48, 95 percentCI 0.35–0.67
*Patients who received prior sorafenib as
the only prior systemic therapy for HCC
HR=Hazard Ratio; CI=Confidence
Interval
Treatment-related grade 3 or 4 adverse events (AEs) that
occurred in at least 5 percent of any patient group were
palmar-plantar erythrodysesthesia, aspartate aminotransferase
increased, hypertension, fatigue, decreased appetite, diarrhea,
asthenia and anemia.
Outcomes in Patients Based on Age [abstract 4090]
The sub-analysis evaluating patients in the CELESTIAL trial
based on age was presented by Lorenza Rimassa, M.D., Humanitas
Clinical and Research Center. In this sub-analysis, patients were
grouped as younger than 65 years of age and 65 years of age and
older. The findings showed OS and PFS were consistently improved
with cabozantinib versus placebo in each age category:
Patients <Age 65 Patients
≥65
Cabozantinib
(n=240)
Placebo
(n=124)
Cabozantinib
(n=230)
Placebo
(n=113)
Median OS (months) 9.6
7.7 11.1 8.3 HR
0.81, 95 percent CI 0.62–1.05 HR 0.74, 95 percent CI
0.56–0.97
Median PFS (months) 5.0
1.9 5.4 2.0
HR 0.45, 95 percent CI 0.35–0.57 HR 0.46, 95
percent CI 0.35–0.59
Treatment-related grade 3 or 4 AEs occurred in at least 5
percent of either age group and were similar in nature and
frequency to the AEs that occurred in patients who received
sorafenib as their only prior systemic therapy.
An encore of the CELESTIAL trial data originally presented at
the 2018 American Society of Clinical Oncology Gastrointestinal
Cancers Symposium (ASCO-GI) will be presented by Dr. Ghassan K.
Abou-Alfa, Memorial Sloan Kettering Cancer Center, during the
Gastrointestinal (Noncolorectal) Cancer Poster Discussion Session
today from 4:45 – 6:00 p.m. CDT in Hall D2 [abstract 4019].
The CELESTIAL trial was the basis for Exelixis’ supplemental New
Drug Application filed with the U.S. Food and Drug Administration
(FDA) for CABOMETYX® (cabozantinib) tablets as a treatment for
patients with previously treated advanced HCC. The Prescription
Drug User Fee Act action date for this application is January 14,
2019. On March 28, 2018, our partner Ipsen announced that they
received validation of the application for variation to the
CABOMETYX marketing authorization from the European Medicines
Agency, the European regulatory authority, for the addition of a
new indication for patients with previously treated advanced
HCC.
About the CELESTIAL Study
CELESTIAL is a phase 3 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 overall survival, and
secondary endpoints include objective response rate and
progression-free survival. Exploratory endpoints include
patient-reported outcomes, biomarkers and safety.
Results of the trial were first presented by Dr. Abou-Alfa at
2018 American Society of Clinical Oncology Gastrointestinal Cancers
Symposium in January 2018.
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.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. HCC is the
fastest-rising cause of cancer-related death in U.S.3 Without
treatment, patients with advanced HCC usually survive less than 6
months.4
About CABOMETYX® (cabozantinib)
CABOMETYX 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 VEGF-targeted therapy, and in the
European Union for previously untreated intermediate- or poor-risk
advanced RCC. 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
and 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 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.
Forward-Looking Statement Disclaimer
This press release contains forward-looking statements,
including, without limitation, statements related to: 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’ hope that cabozantinib will provide a new
treatment option for patients with previously treaded advanced HCC;
plans for an encore presentation of the CELESTIAL trial data,
originally presented at the 2018 ASCO-GI; 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
“continue,” “hope,” “may,” “will,”“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.
_______________________________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
June 2018.2 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 June 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.
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Exelixis, Inc.Investors:Susan Hubbard, 650-837-8194EVP,
Public Affairs and Investor
Relationsshubbard@exelixis.comorMedia:Lindsay Treadway,
650-837-7522Senior Director, Public Affairs and Advocacy
Relationsltreadway@exelixis.com
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