– CABOMETYX is the first therapy to demonstrate
a clinically meaningful and statistically significant
progression-free survival benefit over the current standard of care
–
Exelixis, Inc. (NASDAQ:EXEL) today announced it has completed
the submission of a supplemental New Drug Application (sNDA) to the
U.S. Food and Drug Administration (FDA) for CABOMETYX®
(cabozantinib) tablets as a treatment for patients with previously
untreated advanced renal cell carcinoma (RCC). The sNDA submission
is based on results from the CABOSUN randomized phase 2 trial of
CABOMETYX in patients with previously untreated advanced RCC with
intermediate- or poor-risk disease per the International Metastatic
Renal Cell Carcinoma Database Consortium (IMDC).
“All of us at Exelixis are focused on improving care and
outcomes for patients with cancer. Having successfully launched
CABOMETYX for patients with previously treated advanced RCC, the
submission of this sNDA for CABOMETYX as a treatment in the
first-line RCC setting represents an important milestone for us,”
said Michael M. Morrissey, Ph.D., President and Chief Executive
Officer of Exelixis. “If approved, CABOMETYX will offer an
important new alternative for the treatment of patients with
previously untreated advanced RCC, having demonstrated a clinically
meaningful and statistically significant progression-free survival
benefit over sunitinib, a current standard of care. We would like
to sincerely thank the study 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
bringing us one step closer to our goal of expanding the population
of patients who may benefit from CABOMETYX.”
CABOSUN was conducted by The Alliance for Clinical Trials in
Oncology as part of Exelixis’ collaboration with the National
Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP). On
May 23, 2016, Exelixis announced that CABOSUN met its primary
endpoint, demonstrating a clinically meaningful and statistically
significant improvement in progression-free survival (PFS) compared
with sunitinib in patients with advanced intermediate- or poor-risk
RCC as determined by investigator assessment. These results were
first presented by Dr. Toni Choueiri at the meeting of the European
Society for Medical Oncology 2016, and published in the Journal of
Clinical Oncology (Choueiri, JCO, 2016).1 In June 2017, Exelixis
announced that the analysis of the review by a blinded independent
radiology review committee (IRC) confirmed the primary efficacy
endpoint results of investigator-assessed PFS from the CABOSUN
trial.
An sNDA is an application to the FDA that, if approved, will
allow a drug sponsor to make changes to a previously approved
product label, including modifications to the indication. CABOMETYX
was previously approved by the FDA on April 25, 2016 for the
treatment of patients with advanced RCC who have received prior
anti-angiogenic therapy. The approval was based on results from the
phase 3 METEOR trial, which demonstrated that CABOMETYX provided a
statistically significant and clinically meaningful improvement in
overall survival, PFS and objective response rate as compared with
everolimus in this patient population.
About the CABOSUN StudyCABOSUN 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 and
objective response rate. 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.
Please see Important Safety Information below and full U.S.
prescribing information at
https://cabometyx.com/downloads/cabometyxuspi.pdf.
About Advanced Renal Cell CarcinomaThe 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.5 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.6
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.7,8 These proteins promote tumor
angiogenesis (blood vessel growth), growth, invasiveness and
metastasis.9-12 MET and AXL may provide escape pathways that drive
resistance to VEGF receptor inhibitors.7,8
About CABOMETYX® (cabozantinib)CABOMETYX is
the tablet formulation of cabozantinib. Its targets include MET,
AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has
been shown to inhibit the activity of these receptors, which are
involved in normal cellular function and pathologic processes such
as tumor angiogenesis, invasiveness, metastasis and drug
resistance.
CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The
recommended dose is 60 mg orally, once daily.
On April 25, 2016, the FDA approved CABOMETYX tablets for the
treatment of patients with advanced RCC who have received prior
anti-angiogenic therapy. In February of 2016, Exelixis and Ipsen
jointly announced an exclusive licensing agreement for the
commercialization and further development of cabozantinib
indications outside of the United States, Canada and Japan. This
agreement was amended in December of 2016 to include
commercialization rights for Ipsen in Canada. On September 9, 2016,
the European Commission approved CABOMETYX tablets for the
treatment of advanced RCC in adults who have received prior
vascular endothelial growth factor (VEGF)-targeted therapy in the
European Union, Norway and Iceland. Ipsen has confirmed its intent
to submit the regulatory dossier for cabozantinib as a treatment
for first-line advanced RCC in the European Union in the third
quarter of 2017.
On January 30, 2017, Exelixis and Takeda Pharmaceutical Company
Limited announced an exclusive licensing agreement for the
commercialization and further clinical development of cabozantinib
for all future indications in Japan, including RCC.
CABOMETYX is not indicated for the treatment of previously
untreated advanced RCC.
U.S. Important Safety Information
Hemorrhage: Severe hemorrhage occurred with CABOMETYX.
The incidence of Grade ≥3 hemorrhagic events was 2.1% in
CABOMETYX-treated patients and 1.6% in everolimus-treated patients.
Fatal hemorrhages also occurred in the cabozantinib clinical
program. Do not administer CABOMETYX to patients that have or are
at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: Fistulas
were reported in 1.2% (including 0.6% anal fistula) of
CABOMETYX-treated patients and 0% of everolimus-treated patients.
GI perforations were reported in 0.9% of CABOMETYX-treated patients
and 0.6% of everolimus-treated patients. Fatal perforations
occurred in the cabozantinib clinical program. Monitor patients for
symptoms of fistulas and perforations. Discontinue CABOMETYX in
patients who experience a fistula that cannot be appropriately
managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an
increased incidence of thrombotic events. Venous thromboembolism
was reported in 7.3% of CABOMETYX-treated patients and 2.5% of
everolimus-treated patients. Pulmonary embolism occurred in 3.9% of
CABOMETYX-treated patients and 0.3% of everolimus-treated patients.
Events of arterial thromboembolism were reported in 0.9% of
CABOMETYX-treated patients and 0.3% of everolimus-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. Hypertension was reported in 37% (15% Grade ≥3) of
CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of
everolimus-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: Diarrhea occurred in 74% of patients treated
with CABOMETYX and in 28% of patients treated with everolimus.
Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and
in 2% of everolimus-treated patients. 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. Dose modification due to diarrhea occurred in 26% of
patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES):
Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42%
of patients treated with CABOMETYX and in 6% of patients treated
with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated
patients and in <1% of everolimus-treated patients. Withhold
CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade
3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced
dose. Dose modification due to PPES occurred in 16% of
patients.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
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: CABOMETYX can cause fetal harm
when administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with CABOMETYX and
for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%)
adverse reactions are: diarrhea, fatigue, nausea, decreased
appetite, PPES, hypertension, vomiting, weight decreased, and
constipation.
Drug Interactions: Strong CYP3A4 inhibitors and inducers:
Reduce the dosage of CABOMETYX if concomitant use with strong
CYP3A4 inhibitors cannot be avoided. Increase the dosage of
CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be
avoided.
Lactation: Advise a lactating woman not to breastfeed
during treatment with CABOMETYX and for 4 months after the final
dose.
Reproductive Potential: Contraception―Advise females of
reproductive potential to use effective contraception during
treatment with CABOMETYX and for 4 months after the final dose.
Infertility ―CABOMETYX may impair fertility in females and
males of reproductive potential.
Hepatic Impairment: Reduce the CABOMETYX dose in patients
with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic
impairment. CABOMETYX is not recommended for use in patients with
severe hepatic impairment.
Please see full Prescribing Information at
https://cabometyx.com/downloads/cabometyxuspi.pdf.
About ExelixisExelixis, Inc. (Nasdaq: EXEL) is a
biopharmaceutical company committed to the discovery, development
and commercialization of new medicines to improve care and outcomes
for people with cancer. Since its founding in 1994, three products
discovered at Exelixis have progressed through clinical
development, received regulatory approval, and entered the
marketplace. Two are derived from cabozantinib, an inhibitor of
multiple tyrosine kinases including VEGF, MET, AXL and RET
receptors: CABOMETYX® tablets approved for previously treated
advanced renal cell carcinoma and COMETRIQ® capsules approved for
progressive, metastatic medullary thyroid cancer. The third
product, COTELLIC®, is a formulation of cobimetinib, a reversible
inhibitor of MEK, is marketed under a collaboration with Genentech
(a member of the Roche Group), and is approved as part of a
combination regimen to treat advanced melanoma. Both cabozantinib
and cobimetinib have shown potential in a variety of forms of
cancer and are the subjects of broad clinical development programs.
For more information about Exelixis, please visit www.exelixis.com
or follow @ExelixisInc on Twitter.
Forward-Looking Statement DisclaimerThis press release
contains forward-looking statements, including, without limitation,
statements related to Exelixis' focus and commitment to the
discovery, development and commercialization of new medicines with
the potential to improve care and outcomes for people with cancer;
the potential of cabozantinib to benefit patients with
previously-untreated advanced RCC; Exelixis’ focus on further
developing cabozantinib and advancing closer to its goal of
expanding the population of patients who may benefit from
cabozantinib; the intent of Exelixis’ partner, Ipsen, to submit the
regulatory dossier for cabozantinib as a treatment for first-line
advanced RCC in the EU in the third quarter of 2017; and
cobimetinib’s continued development and its potential in a variety
of forms of cancer. Words such as “will,” “may,” “intends,”
“committed,” “potential,” 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 availability
of data at the referenced times; risks related to the potential
failure of cabozantinib to demonstrate safety and efficacy in
clinical testing; risks and uncertainties related to regulatory
review and approval processes and Exelixis’ compliance with
applicable legal and regulatory requirements; Exelixis’ dependence
on its relationship with Genentech/Roche with respect to
cobimetinib and Exelixis’ ability to maintain its rights under the
collaboration; 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 May
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.
References:
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. Journal of Clinical Oncology. 2016; 35:6,
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. Journal of
Clinical Oncology. 2009; 27:5794-5799. 3. American Cancer Society.
Cancer Facts & Figures 2017. Atlanta: American Cancer Society;
2017. 4. Jonasch, E., Gao, J., Rathmell, W., Renal cell carcinoma.
BMJ. 2014; 349:g4797. 5. Ko, J. , Choueiri, T., et al. First-,
second- third-line therapy for mRCC: benchmarks for trial design
from the IMDC. British Journal of Cancer. 2014; 110:1917-1922. 6.
Decision Resources Report: Renal Cell Carcinoma. October 2014
(internal data on file). 7. Harshman, L., and Choueiri, T.,
Targeting the hepatocyte growth factor/c-Met signaling pathway in
renal cell carcinoma. Cancer J. 2013; 19(4):316-323. 8. 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(37):13373-13378. 9. 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. 10.
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(9):5902–5912. 11. 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. 12. 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.
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Exelixis, Inc.Investors:Susan Hubbard, 650-837-8194EVP,
Public Affairs and Investor
Relationsshubbard@exelixis.comorMedia:Lindsay Treadway,
650-837-7522Director, Public Affairs and Advocacy
Relationsltreadway@exelixis.com
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