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Exelixis Submits U.S. Supplemental New Drug Application for CABOMETYX® (cabozantinib) for the Treatment of Previously Untreated Advanced Kidney Cancer

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– 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 Study
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 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 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.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 Exelixis
Exelixis, 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 Disclaimer
This 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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