– COSMIC-313 is the third phase 3 pivotal trial to investigate
cabozantinib in combination with immune checkpoint inhibitors –
ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis,
Inc. (NASDAQ: EXEL) today announced that it is initiating
COSMIC-313, a phase 3 pivotal trial of cabozantinib (CABOMETYX®) in
combination with nivolumab (Opdivo®) and ipilimumab (Yervoy®) versus
nivolumab and ipilimumab in patients with previously untreated advanced
renal cell carcinoma (RCC) with intermediate- or poor-risk disease per
the International Metastatic Renal Cell Carcinoma Database Consortium.
The primary endpoint of the trial is progression-free survival, and the
secondary endpoints are overall survival and objective response rate.
“Clinical observations suggest cabozantinib promotes an
immune-permissive environment, which could present an opportunity for
additive or synergistic effects with immune checkpoint inhibitors,” said
Gisela Schwab, M.D., President, Product Development and Medical Affairs
and Chief Medical Officer, Exelixis. “The mechanisms of action of single
agent cabozantinib and the combination of nivolumab and ipilimumab are
complementary, and each has demonstrated efficacy in advanced renal cell
carcinoma. The further combination of these agents as a triplet regimen
may offer promise to previously untreated patients with intermediate- or
poor-risk disease, who are known to have poor treatment outcomes.”
COSMIC-313 is a multicenter, randomized, double-blinded, controlled
phase 3 pivotal trial that aims to enroll approximately 676 patients at
150 sites globally. Patients will be randomized 1:1 to the experimental
arm of cabozantinib in combination with nivolumab and ipilimumab and to
the control arm of nivolumab and ipilimumab in combination with matched
placebo.
Design of this phase 3 pivotal trial was informed by results from the
ongoing phase 1b study of cabozantinib plus nivolumab with or without
ipilimumab in patients with previously treated advanced genitourinary
cancers, including RCC. The phase 1b trial is being conducted by the
U.S. National Cancer Institute and includes centers from its
Experimental Therapeutics Clinical Trials Network.
Bristol-Myers Squibb is providing nivolumab and ipilimumab for use in
this trial.
Please see Important Safety Information below and full U.S. prescribing
information at https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About RCC
The American Cancer Society’s 2019 statistics cite kidney cancer as
among the top ten most commonly diagnosed forms of cancer among both men
and women in the U.S.1 Clear cell RCC is the most common type
of kidney cancer in adults.2 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.1
Approximately 32,000 patients in the U.S. and 70,000 globally require
treatment, and an estimated 15,000 patients in the U.S. each year are in
need of a first-line treatment for advanced kidney cancer.3
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.4,5 These proteins promote tumor angiogenesis
(blood vessel growth), growth, invasiveness and metastasis.6,7,8,9
MET and AXL may provide escape pathways that drive resistance to VEGF
receptor inhibitors.5,6
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced RCC and for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated with
sorafenib. 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 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.
The combination of CABOMETYX with nivolumab and ipilimumab is not
indicated for previously untreated advanced RCC.
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. Our discovery efforts
have resulted in four marketed 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 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 opportunity for the
combination of cabozantinib with immune checkpoint inhibitors to produce
additive or synergistic effects; the potential of the triplet
combination of cabozantinib, nivolumab and ipilimumab to offer promise
to previously untreated patients with intermediate- or poor-risk
advanced RCC; 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: risks and uncertainties related to
regulatory review and approval processes and Exelixis’ compliance with
applicable legal and regulatory requirements; the potential failure of
the triplet combination of cabozantinib, nivolumab and ipilimumab to
demonstrate safety and/or efficacy in COSMIC-313; uncertainties inherent
in the product development process, including evolving regulatory
requirements, slower than anticipated patient enrollment or inability to
identify a sufficient number of clinical trial sites; the costs of
conducting clinical trials, including the ability or willingness of
Exelixis’ collaboration partners to invest in the resources necessary to
complete the trials; Exelixis’ dependence on third-party vendors for the
development, manufacture and supply of cabozantinib; Exelixis’ ability
to protect its intellectual property rights; market competition; changes
in economic and business conditions; and other factors
affecting Exelixis and its development programs discussed under the
caption “Risk Factors” in Exelixis’ Annual Report on Form 10-K filed
with the Securities and Exchange Commission (SEC) on February 22, 2019,
and in Exelixis’ future filings with the SEC, including, without
limitation, Exelixis’ Quarterly Report on Form 10-Q expected to be filed
with the SEC on May 1, 2019. 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. MINNEBRO is a Japanese trademark.
_____________________________
1 American Cancer Society:
Cancer Facts & 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 May 2019.
2 Jonasch, E., Gao, J., Rathmell, W.,
Renal cell carcinoma. BMJ. 2014; 349:g4797.
3
Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal
data on file).
4 Harshman, L., and Choueiri, T.
Targeting the hepatocyte growth factor/c-Met signaling pathway in renal
cell carcinoma. Cancer J. 2013; 19:316-323.
5
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.
6 Zhou, L., Liu, X-D., Sun, M.,
et al. Targeting MET and AXL overcomes resistance to sunitinib therapy
in renal cell carcinoma. Oncogene. 2016; 35:2687-2697.
7
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.
8 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.
9 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. 1997; 79:681-687.
Contacts
Investors:
Susan Hubbard
EVP, Public Affairs
and
Investor Relations
Exelixis, Inc.
(650)
837-8194
shubbard@exelixis.com
Media:
Lindsay
Treadway
Senior Director, Public Affairs and Advocacy
Relations
Exelixis, Inc.
(650) 837-7522
ltreadway@exelixis.com