Inc. (Nasdaq:EXEL) today announced that its partner Ipsen received
approval from the European Commission (EC) for CABOMETYX®
(cabozantinib) 20 mg, 40 mg and 60 mg for the first-line treatment of
adults with intermediate- or poor-risk advanced renal cell carcinoma
(RCC) in the European Union.
“The expanded marketing authorization of CABOMETYX to include previously
untreated patients in Europe with intermediate- or poor-risk advanced
kidney cancer is an exciting milestone for a patient population in need
of more treatment options,” said Michael M. Morrissey, Ph.D., President
and Chief Executive Officer of Exelixis. “We look forward to our
continued collaboration with our partners Ipsen and Takeda to bring new
options to more patients with difficult-to-treat cancers in Europe and
around the world.”
Under the terms of the Collaboration and License Agreement with Ipsen,
Exelixis will receive a milestone payment of $50 million for the EC
approval, of which approximately $46 million was recognized as
collaboration revenue in the first quarter of 2018. The payment will be
made by Ipsen within the next 70 days.
CABOMETYX was approved in the European Union in September 2016 for the
treatment of advanced RCC in adults following prior vascular endothelial
growth factor (VEGF)-targeted therapy. The expanded EC approval to
include first-line treatment is based on results of the CABOSUN trial,
which met its primary endpoint of improved progression-free survival
(PFS) compared with sunitinib in patients with previously untreated
advanced RCC determined to be intermediate- or poor-risk by the
International Metastatic RCC Database Consortium (IMDC) criteria. In
December 2017, the U.S. Food and Drug Administration (FDA) approved
CABOMETYX for the expanded indication of patients with advanced RCC
based on the results from the CABOSUN trial.
Please see Important Safety Information below and full U.S. prescribing
information at https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About the CABOSUN Study
On May 23, 2016, Exelixis announced that the phase 2 CABOSUN study met
its primary endpoint, demonstrating a statistically significant and
clinically meaningful improvement in PFS compared with sunitinib in
patients with advanced intermediate- or poor-risk RCC as determined by
investigator assessment. The CABOSUN study was conducted by The Alliance
for Clinical Trials in Oncology and was sponsored by the National Cancer
Institute-Cancer Therapy Evaluation Program (NCI-CTEP) under the
Cooperative Research and Development Agreement with Exelixis for the
development of cabozantinib. These results were first presented by Dr.
Toni Choueiri at the European Society for Medical Oncology (ESMO) 2016
Congress, and published in the Journal of Clinical Oncology
(Choueiri, JCO, 2016).1 In June 2017, a blinded
independent radiology review committee (IRC) confirmed that cabozantinib
provided a clinically meaningful and statistically significant
improvement in the primary efficacy endpoint of investigator-assessed
PFS. Results from the IRC review were presented by Dr. Toni Choueiri at
the ESMO 2017 Congress.
CABOSUN was a randomized, open-label, active-controlled phase 2 trial
that enrolled 157 patients with advanced RCC determined to be
intermediate- or poor-risk by the IMDC criteria. Patients were
randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib
(50 mg once daily, 4 weeks on followed by 2 weeks off). The primary
endpoint was PFS. Secondary endpoints included overall survival,
objective response rate and safety. Eligible patients were required to
have locally advanced or metastatic clear-cell RCC, ECOG performance
status 0-2 and had to be intermediate- or poor-risk per the IMDC
criteria (Heng, JCO, 2009).2 Prior systemic treatment
for RCC was not permitted.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2018 statistics cite kidney cancer as
among the top ten most commonly diagnosed forms of cancer among both men
and women in the U.S.3 Clear cell RCC is the most common type
of kidney cancer in adults.4 If detected in its early stages,
the five-year survival rate for RCC is high; for patients with advanced
or late-stage metastatic RCC, however, the five-year survival rate is
only 12 percent, with no identified cure for the disease.3
Approximately 30,000 patients in the U.S. and 68,000 globally require
treatment, and an estimated 14,000 patients in the U.S. each year are in
need of a first-line treatment for advanced kidney cancer.5
The majority of clear cell RCC tumors have lower than normal levels of a
protein called von Hippel-Lindau, which leads to higher levels of MET,
AXL and VEGF.6,7 These proteins promote tumor angiogenesis
(blood vessel growth), growth, invasiveness and metastasis.8,9,10,11
MET and AXL may provide escape pathways that drive resistance to VEGF
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. Regulatory
applications were recently submitted for CABOMETYX for additional
advanced hepatocellular carcinoma (HCC) indications: on March 15, 2018,
Exelixis announced the completed submission of a supplemental New Drug
Application to the U.S. FDA for CABOMETYX for previously treated
patients with advanced HCC; 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
hepatocellular carcinoma 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.
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,
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
CABOMETYX as a treatment for patients in Europe with intermediate- or
poor-risk advanced RCC; Exelixis’ plan to work with Ipsen and Takeda to
bring new treatment options to more patients with difficult-to-treat
cancers in Europe and around the world; the timing for receipt and
related revenue recognition requirements of the $50 million milestone
payment from Ipsen to Exelixis for the approval of the first-line
treatment of RCC; 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 “continued,” “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: the degree of market acceptance of CABOMETYX, COMETRIQ, and
COTELLIC and the availability of sufficient coverage and adequate
reimbursement for these products; Exelixis’ dependence on its
relationships with its collaboration partners, including the level of
their investment in the resources necessary to successfully
commercialize partnered compounds in the territories where they are
approved; risks and uncertainties related to regulatory review and
approval processes and Exelixis’ compliance with applicable regulatory
and legal requirements; risks related to the potential failure of
cabozantinib and cobimetinib, both alone and in combination with other
therapies, to demonstrate safety and efficacy in clinical testing; the
availability of data at the referenced times; 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; 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 its
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’ quarterly 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 and CABOMETYX are registered U.S.
1 Choueiri, T.K., et al. Cabozantinib versus Sunitinib as
Initial Targeted Therapy for Patients with Metastatic Renal Cell
Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN
Trial. Am J Clin Oncol. 2016; 35:591-597.
2 Heng D.Y., Xie W., Regan M.M., et al. Prognostic factors
for overall survival in patients with metastatic renal cell carcinoma
treated with vascular endothelial growth factor-targeted agents: Results
from a large, multicenter study. Am J Clin Oncol. 2009;
3 American Cancer Society. Cancer Facts & Figures 2018.
Atlanta: American Cancer Society; 2018.
4 Jonasch, E., Gao, J., Rathmell, W. Renal cell carcinoma. BMJ.
5 Decision Resources Report: Renal Cell Carcinoma. October
2014 (internal data on file).
6 Harshman, L., and Choueiri, T. Targeting the hepatocyte
growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer
J. 2013; 19:316-323.
7 Rankin, et al. Direct regulation of GAS6/AXL signaling by
HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci
USA. 2014; 111:13373-13378.
8 Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL
overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene.
9 Koochekpour, et al. The von Hippel-Lindau tumor suppressor
gene inhibits hepatocyte growth factor/scatter factor-induced invasion
and branching morphogenesis in renal carcinoma cells. Mol Cell Biol.
10 Takahashi, A., Sasaki, H., Kim, S., et al. Markedly
increased amounts of messenger RNAs for vascular endothelial growth
factor and placenta growth factor in renal cell carcinoma associated
with angiogenesis. Cancer Res. 1994; 54:4233-4237.
11 Nakagawa, M., Emoto, A., Hanada, T., Nasu, N., Nomura, Y.
Tubulogenesis by microvascular endothelial cells is mediated by vascular
endothelial growth factor (VEGF) in renal cell carcinoma. Br J Urol.
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