– Approval is based on COSMIC-311 trial, in
which CABOMETYX demonstrated significant improvement in
progression-free survival versus placebo –
Exelixis, Inc. (Nasdaq: EXEL) today announced that its partner
Ipsen received approval from the European Commission (EC) for
CABOMETYX® (cabozantinib) as a monotherapy for the treatment of
adult patients with locally advanced or metastatic differentiated
thyroid carcinoma (DTC), refractory or not eligible to radioactive
iodine (RAI) who have progressed during or after prior systemic
therapy. This approval allows for the marketing of CABOMETYX in
this indication in all 27 member states of the European Union,
Norway, Liechtenstein and Iceland.
“We are excited that CABOMETYX will now be available in Europe
for patients with locally advanced or metastatic differentiated
thyroid carcinoma who have progressed during or after prior
systemic therapy, that previously had no approved standard
treatment options,” said Vicki L. Goodman, M.D., Executive Vice
President, Product Development and Medical Affairs, and Chief
Medical Officer, Exelixis. “The European Commission approval is an
additional step in our partnership with Ipsen to provide new
treatment options for more eligible patients with
difficult-to-treat cancer types.”
The EC approval is based on results from COSMIC-311, the phase 3
pivotal trial that demonstrated significant improvement in
progression-free survival (PFS) with CABOMETYX versus placebo in
patients with RAI-refractory DTC who progressed after up to two
prior VEGFR-targeted therapies. COSMIC-311 was the basis for the
U.S. Food and Drug Administration (FDA) approval of CABOMETYX in
September 2021 for the treatment of adult and pediatric patients 12
years of age and older with locally advanced or metastatic DTC that
has progressed following VEGFR-targeted therapy and who are
RAI-refractory or ineligible.
CABOMETYX is also approved in the European Union as a
monotherapy for the treatment of advanced renal cell carcinoma
(RCC) in adults who have received prior VEGFR-targeted therapy, for
previously untreated intermediate- or poor-risk advanced RCC and
for hepatocellular carcinoma (HCC) in adults who have been
previously treated with sorafenib. CABOMETYX in combination with
OPDIVO® (nivolumab) is approved as a first-line treatment for
advanced RCC.
About COSMIC-311
COSMIC-311 was a multicenter, randomized, double-blind,
placebo-controlled phase 3 pivotal trial that enrolled 258 patients
at 164 sites globally. Patients were randomized in a 2:1 ratio to
receive either CABOMETYX 60 mg or placebo once daily. The primary
endpoints were PFS and objective response rate. Exelixis is
sponsoring COSMIC-311, and Ipsen is co-funding the trial. More
information about this trial is available at
ClinicalTrials.gov.
About DTC
In 2020, over 580,000 new cases of thyroid cancer were diagnosed
worldwide.1 Approximately 44,000 new cases of thyroid cancer will
be diagnosed in the U.S. in 2022. Nearly three out of four of these
cases will be in women, and the disease is more commonly diagnosed
at a younger age compared with most other adult cancers. While
cancerous thyroid tumors include differentiated, medullary and
anaplastic forms, differentiated thyroid tumors make up about 90%
of cases and includes papillary, follicular and Hürthle cell
cancer.2 DTC is typically treated with surgery followed by ablation
of the remaining thyroid with RAI, but approximately 5% to 15% of
cases are resistant to RAI treatment.3,4 For these patients, life
expectancy is only three to six years from the time metastatic
lesions are detected.5,6,7
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced RCC; for the treatment of patients with HCC
who have been previously treated with sorafenib; for patients with
advanced RCC as a first-line treatment in combination with
nivolumab; and for adult and pediatric patients 12 years of age and
older with locally advanced or metastatic DTC that has progressed
following prior VEGFR-targeted therapy and who are RAI-refractory
or ineligible. CABOMETYX tablets have also received regulatory
approvals in the European Union and additional countries and
regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights
for the commercialization and further clinical development of
cabozantinib outside of the U.S. and Japan. Under the terms of the
license agreement with Ipsen, Exelixis is eligible to receive
development, regulatory and sales milestone payments from Ipsen and
further receive royalties on net sales of cabozantinib by Ipsen
outside of the U.S. 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. Exelixis holds the exclusive
rights to develop and commercialize cabozantinib in the U.S.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with
CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5%
in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue
CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as
recommended. Do not administer CABOMETYX to patients who have a
recent history of hemorrhage, including hemoptysis, hematemesis, or
melena.
Perforations and Fistulas: Fistulas, including fatal
cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI)
perforations, including fatal cases, occurred in 1% of CABOMETYX
patients. Monitor patients for signs and symptoms of fistulas and
perforations, including abscess and sepsis. Discontinue CABOMETYX
in patients who experience a Grade 4 fistula 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
events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause
hypertension, including hypertensive crisis. Hypertension was
reported in 37% (16% 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. Permanently discontinue CABOMETYX for
severe hypertension that cannot be controlled with
anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients.
Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and
manage patients using antidiarrheals as indicated. Withhold
CABOMETYX until improvement to ≤ Grade 1, resume at a reduced
dose.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in
45% 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.
Hepatotoxicity: CABOMETYX in combination with nivolumab
can cause hepatic toxicity with higher frequencies of Grades 3 and
4 ALT and AST elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of and periodically
throughout treatment. Consider more frequent monitoring of liver
enzymes than when the drugs are administered as single agents. For
elevated liver enzymes, interrupt CABOMETYX and nivolumab and
consider administering corticosteroids.
With the combination of CABOMETYX and nivolumab, Grades 3 and 4
increased ALT or AST were seen in 11% of patients. ALT or AST >3
times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%)
received systemic corticosteroids; ALT or AST resolved to Grades
0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT
or AST who were rechallenged with either CABOMETYX (n=9) or
nivolumab (n=11) as a single agent or with both (n=24), recurrence
of Grade ≥2 increased ALT or AST was observed in 2 patients
receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients
receiving both CABOMETYX and nivolumab. Withhold and resume at a
reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with
nivolumab can cause primary or secondary adrenal insufficiency. For
Grade 2 or higher adrenal insufficiency, initiate symptomatic
treatment, including hormone replacement as clinically indicated.
Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a
reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with
RCC who received CABOMETYX with nivolumab, including Grade 3
(2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency
led to permanent discontinuation of CABOMETYX and nivolumab in 0.9%
and withholding of CABOMETYX and nivolumab in 2.8% of patients with
RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency
received hormone replacement therapy, including systemic
corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the
15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was
withheld for adrenal insufficiency, 6 reinstated treatment after
symptom improvement; of these, all (n=6) received hormone
replacement therapy and 2 had recurrence of adrenal
insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX
patients. Monitor urine protein regularly during CABOMETYX
treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until
improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced
dose. 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 3 weeks prior to scheduled dental
surgery or invasive dental procedures, if possible. Withhold
CABOMETYX for development of ONJ until complete resolution, resume
at a reduced dose.
Impaired Wound Healing: Wound complications occurred with
CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to
elective surgery. Do not administer CABOMETYX for at least 2 weeks
after major surgery and until adequate wound healing. The safety of
resumption of CABOMETYX after resolution of wound healing
complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
RPLS, a syndrome of subcortical vasogenic edema diagnosed by
characteristic findings 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.
Thyroid Dysfunction: Thyroid dysfunction, primarily
hypothyroidism, has been observed with CABOMETYX. Based on the
safety population, thyroid dysfunction occurred in 19% of patients
treated with CABOMETYX, including Grade 3 in 0.4% of patients.
Patients should be assessed for signs of thyroid dysfunction
prior to the initiation of CABOMETYX and monitored for signs and
symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid
function testing and management of dysfunction should be performed
as clinically indicated.
Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on
the safety population, hypocalcemia occurred in 13% of patients
treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1%
of patients. Laboratory abnormality data were not collected in
CABOSUN.
In COSMIC-311, hypocalcemia occurred in 36% of patients treated
with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of
patients.
Monitor blood calcium levels and replace calcium as necessary
during treatment. Withhold and resume at reduced dose upon recovery
or permanently discontinue CABOMETYX depending on severity.
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 common (≥20%) adverse reactions are:
CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased
appetite, hypertension, nausea, vomiting, weight decreased,
constipation.
CABOMETYX in combination with nivolumab: diarrhea, fatigue,
hepatotoxicity, PPE, stomatitis, rash, hypertension,
hypothyroidism, musculoskeletal pain, decreased appetite, nausea,
dysgeusia, abdominal pain, cough, and upper respiratory tract
infection.
DRUG INTERACTIONS
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.
USE IN SPECIFIC POPULATIONS
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. Avoid CABOMETYX in
patients with severe hepatic impairment.
Please see accompanying full Prescribing Information
https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf.
You are encouraged to report negative side effects of
prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call
1-800-FDA-1088.
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 system genetics, 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. Our discovery efforts have resulted in four commercially
available products, CABOMETYX® (cabozantinib), COMETRIQ®
(cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO®
(esaxerenone), and we 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 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.
Forward-Looking Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: the
therapeutic and commercial potential of CABOMETYX as a monotherapy
for adult patients with RAI-refractory or ineligible DTC who have
progressed during or after prior systemic therapy; Exelixis’ and
Ipsen’s shared goal of providing new treatment options for more
eligible patients with difficult-to-treat cancer types; 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 that CABOMETYX
may achieve in the European Union; Exelixis’ dependence on its
relationship with Ipsen, including Ipsen’s investment in the
resources necessary to successfully commercialize CABOMETYX in the
European Union; Exelixis’ and Ipsen’s ability to maintain and scale
adequate sales, marketing, market access and product distribution
capabilities for CABOMETYX or to enter into and maintain agreements
with third parties to do so; Exelixis’ and Ipsen’s continuing
compliance with applicable legal and regulatory requirements; the
COVID-19 pandemic and other global events and their impacts on
Exelixis’ and Ipsen’s commercial activities; Exelixis’ ability to
protect its intellectual property rights; Exelixis’ dependence on
third-party vendors for the development, 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 and its commercial programs and partnerships
discussed under the caption “Risk Factors” in Exelixis’ Annual
Report on Form 10-K filed with the Securities and Exchange
Commission (SEC) on February 18, 2022, 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, except as required by law.
Exelixis, the Exelixis logo, CABOMETYX and
COMETRIQ are registered U.S. trademarks of Exelixis. COTELLIC is a
registered trademark of Genentech, Inc. MINNEBRO is a registered
trademark of Daiichi Sankyo Company, Limited. OPDIVO® is a
registered trademark of Bristol-Myers Squibb Company.
1 Sung. H et al. Global cancer statistics 2020: GLOBOCAN
estimates of incidence and mortality worldwide for 36 cancers in
185 countries. CA: A Cancer Journal For Clinicians. doi:
10.3322/caac.21660. 2 American Cancer Society. About Thyroid
Cancer. Available at:
https://www.cancer.org/cancer/thyroid-cancer/about.html. Accessed
May 2022. 3 UpToDate. Differentiated thyroid cancer: Overview of
management. Available at:
https://www.uptodate.com/contents/differentiated-thyroid-cancer-overview-of-management.
Accessed May 2022. 4 Worden F. 2014. Treatment strategies for
radioactive iodine-refractory differentiated thyroid cancer. Ther
Adv Med Oncol. 6:267–279. 5 Xing M, Haugen BR, Schlumberger M.
2013. Progress in molecular-based management of differentiated
thyroid cancer. Lancet. 381:1058–1069. 6 Pacini F, et al. 2012.
Radioactive iodine-refractory differentiated thyroid cancer: unmet
needs and future directions. Expert Rev Endocrinol Metab.
7:541–554. 7 Durante C, et al. 2006. Long-term outcome of 444
patients with distant metastases from papillary and follicular
thyroid carcinoma: benefits and limits of radioiodine therapy. J
Clin Endocrinol Metab. 91:2892–2899.
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version on businesswire.com: https://www.businesswire.com/news/home/20220502005717/en/
Investors: Susan Hubbard EVP, Public Affairs and Investor
Relations Exelixis, Inc. (650) 837-8194 shubbard@exelixis.com
Media: Lindsay Treadway Executive Director, Public
Affairs and Advocacy Relations Exelixis, Inc. (650) 837-7522
ltreadway@exelixis.com
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