– Approval expands indication and comes well in advance of PDUFA
date of February 15, 2018 –
– Exelixis prepared to fully support expanded indication
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Dec. 19, 2017--
Inc. (NASDAQ:EXEL) today announced that the U.S. Food and Drug
Administration (FDA) approved CABOMETYX® (cabozantinib)
tablets for the expanded indication of patients with advanced renal cell
carcinoma (RCC). RCC is the most common form of kidney cancer in adults.
The FDA’s priority review and approval of CABOMETYX was based on results
from the randomized phase 2 CABOSUN trial in patients with previously
untreated RCC, which demonstrated a statistically significant and
clinically meaningful improvement in progression-free survival (PFS)
versus sunitinib, a current standard of care. Today’s label expansion
follows the initial FDA approval of CABOMETYX in April 2016 for the
treatment of patients with advanced RCC who have previously received
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“Today’s approval of CABOMETYX is a true win for patients in the U.S.
with advanced renal cell carcinoma who now have a new first-line
treatment option,” said Michael M. Morrissey, Ph.D., President and Chief
Executive Officer of Exelixis. “We are very pleased with the expanded
indication and are prepared to bring CABOMETYX to all eligible patients
who may benefit from this important treatment option starting today. I
would like to sincerely thank the patients and clinicians who
participated in the CABOSUN trial, the Alliance and NCI-CTEP, as well as
our dedicated clinical, medical and regulatory teams for their tireless
efforts to this end. We would also like to acknowledge the review team
at FDA for their expeditious review of our application.”
“The CABOSUN trial enrolled treatment-naïve patients with advanced
kidney cancer, including those who are known to fare poorly, such as
patients with intermediate- or poor-prognostic factors and those with
bone metastases or multiple sites of metastatic disease,” said Toni
Choueiri, M.D., Director, Lank Center for Genitourinary Oncology,
Dana-Farber Cancer Institute. “Physicians are already experienced in
using CABOMETYX in the second-line advanced RCC setting, and it is a
much-needed advance to also now have CABOMETYX as an option for their
patients with previously untreated advanced RCC.”
The expanded approval of CABOMETYX is based on results of the phase 2
CABOSUN trial, which met its primary endpoint of improving PFS.
According to the independent radiology review committee analysis of the
data, CABOMETYX demonstrated a clinically meaningful and statistically
significant 52 percent reduction in the rate of disease progression or
death (HR 0.48, 95% CI 0.31-0.74, two-sided P=0.0008). Median PFS for
CABOMETYX was 8.6 months versus 5.3 months for sunitinib, corresponding
to a 3.3 month (62 percent) improvement.
All causality grade 3 or 4 adverse reactions occurred in 68 percent of
patients receiving CABOMETYX and 65 percent of patients receiving
sunitinib. The most frequent all causality Grade 3-4 adverse reactions
(≥5 percent) in patients treated with CABOMETYX were hypertension,
diarrhea, hyponatremia, hypophosphatemia, palmar-plantar
erythrodysesthesia (PPE), fatigue, increased ALT, decreased appetite,
stomatitis, pain, hypotension, and syncope. Twenty-one percent of
patients in the CABOMETYX arm compared to 22 percent of patients
receiving sunitinib discontinued treatment due to adverse events.
“We at the Alliance for Clinical Trials in Oncology are very gratified
that the CABOSUN study supported the approval of CABOMETYX for the
potential first-line treatment of all patients with advanced renal cell
carcinoma. This trial exemplifies how NCI-sponsored studies can be
efficient, accrue rapidly, and yield results highly relevant to the
field,” said Michael J. Morris, M.D., medical oncologist at Memorial
Sloan Kettering Cancer Center, and Chair of the Alliance Genitourinary
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 CABOSUN 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 2017 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.8-11
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 and Switzerland 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.
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 them 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
or follow @ExelixisInc on Twitter.
Forward-Looking Statement Disclaimer
This press release contains forward-looking statements, including,
without limitation, statements related to: the impact of the FDA’s
approval of CABOMETYX as a treatment for patients with previously
untreated advanced renal cell carcinoma; Exelixis’ preparedness to bring
CABOMETYX to the entire RCC patient community immediately; revenue
growth from CABOMETYX, COMETRIQ, and COTELLIC 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; and Exelixis’ mission to deliver the next
generation of Exelixis medicines and help patients recover stronger and
live longer. Words such as “prepared,” “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 Exelixis’ compliance with
applicable legal and regulatory requirements; risks related to the
potential failure of cabozantinib to demonstrate safety and additional
efficacy in clinical testing; Exelixis’ ability to conduct clinical
trials of cabozantinib sufficient to achieve a positive completion;
Exelixis’ dependence on its relationships with its cabozantinib
collaboration partners, including, the level of their investment in the
resources necessary to successfully commercialize cabozantinib in the
territories where it is 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 and other activities;
Exelixis’ dependence on its relationship with Genentech/Roche with
respect to cobimetinib and Exelixis’ ability to maintain its rights
under the collaboration; Exelixis’ dependence on third-party vendors;
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’
quarterly report on Form 10-Q filed with the Securities and Exchange
Commission(SEC) on November 1, 2017, 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.
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.
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:
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American Cancer Society; 2017.
Jonasch, E., Gao, J., Rathmell, W. Renal cell carcinoma. BMJ.
Decision Resources Report: Renal Cell Carcinoma. October 2014
(internal data on file).
Harshman, L., and Choueiri, T. Targeting the hepatocyte growth
factor/c-Met signaling pathway in renal cell carcinoma. Cancer J.
Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF
promotes renal metastasis through SRC and MET. Proc Natl Acad
Sci U S A. 2014; 111:13373-13378.
Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL
overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene.
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. 1999; 19:5902–5912.
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.
Nakagawa, M., Emoto, A., Hanada, T., Nasu, N., Nomura, Y.
Tubulogenesis by microvascular endothelial cells is mediated by
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Source: Exelixis, Inc.
Public Affairs and Investor Relations
Director, Public Affairs
and Advocacy Relations