– CABOMETYX is the first and only therapy
approved in the European Union to demonstrate improved overall
survival, progression-free survival and objective response rate in
a large, randomized phase 3 trial of patients with advanced kidney
cancer –
– Approval of CABOMETYX in European Union
triggers $60 million milestone payment to Exelixis under licensing
agreement with Ipsen –
Exelixis, Inc. (NASDAQ:EXEL) today announced that the European
Commission (EC) has approved CABOMETYX™ (cabozantinib) tablets for
the treatment of advanced renal cell carcinoma (RCC) in adults
following prior vascular endothelial growth factor (VEGF)-targeted
therapy. CABOMETYX was granted accelerated assessment by the
European Medicines Agency, and is the first therapy to demonstrate
in a phase 3 trial for patients with advanced RCC, robust and
clinically meaningful improvements in all three key efficacy
parameters — overall survival (OS), progression-free survival (PFS)
and objective response rate (ORR). This approval allows for the
marketing of CABOMETYX in all 28 member states of the European
Union, Norway and Iceland.
EC approval of CABOMETYX triggers a $60 million milestone
payment to Exelixis under the licensing agreement with Ipsen for
the commercialization and further development of CABOMETYX
indications outside of the United
States, Canada and Japan. The approval is based on
the results of the large, randomized phase 3 METEOR trial.
“The marketing authorization of CABOMETYX by the European
Commission to treat patients with advanced renal cell carcinoma
reflects the strong efficacy results observed with cabozantinib in
the phase 3 METEOR trial, and is an important milestone in our
collaboration with Ipsen,” said Michael M. Morrissey, Ph.D.,
president and chief executive officer of Exelixis. “This marketing
authorization helps address an unmet medical need in Europe by
providing patients with a new therapy that slows disease
progression and prolongs overall survival. We look forward to
further examining the use of CABOMETYX in earlier lines of therapy
and in other difficult-to-treat cancers.”
About CABOMETYX™ (cabozantinib)
CABOMETYX is the tablet formulation of cabozantinib. CABOMETYX
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, the U.S. FDA approved CABOMETYX tablets for the
treatment of patients with advanced renal cell carcinoma who have
received prior anti-angiogenic therapy. On September 9, 2016, the
European Commission approved CABOMETYX tablets for the treatment of
advanced renal cell carcinoma in adults who have received prior
vascular endothelial growth factor (VEGF)-targeted therapy in the
European Union, Norway and Iceland.
On February 29, 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.
About the METEOR Phase 3 Pivotal Trial
METEOR was an open-label, event-driven trial of 658 patients
with advanced renal cell carcinoma who had failed at least one
prior VEGFR TKI therapy. The primary endpoint was PFS in the first
375 patients randomized. Secondary endpoints included OS and
objective response rate in all enrolled patients. The trial was
conducted at approximately 200 sites in 26 countries, and
enrollment was weighted toward Western Europe, North America, and
Australia. Patients were randomized 1:1 to receive 60 mg of
CABOMETYX daily or 10 mg of everolimus daily and were stratified
based on the number of prior VEGFR TKI therapies received and on
MSKCC risk criteria. No cross-over was allowed between the study
arms.
METEOR met its primary endpoint by significantly improving PFS.
Compared with everolimus, CABOMETYX was associated with a 42
percent reduction in the rate of disease progression or death.
Median PFS for CABOMETYX was 7.4 months versus 3.8 months for
everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). CABOMETYX also
significantly improved the objective response rate compared with
everolimus, be it through investigator assessment (24% versus 4%,
p<0.0001) or through central review (17% versus 3%, p <
0.0001). These data were presented at the European Cancer Congress
in September 2015 and published in The New England Journal of
Medicine.1
CABOMETYX also demonstrated a statistically significant and
clinically meaningful increase in OS in the METEOR trial. Compared
with everolimus, CABOMETYX was associated with a 34 percent
reduction in the rate of death. Median OS was 21.4 months for
patients receiving CABOMETYX versus 16.5 months for those receiving
everolimus (HR=0.66, 95% CI 0.53-0.83, P=0.0003).
CABOMETYX benefit in OS was robust and consistent across all
pre-specified subgroups. In particular, benefit was observed
regardless of risk category, location and extent of tumor
metastases, and tumor MET expression level. These results were
presented on June 5, 2016 at the ASCO Annual Meeting and
concurrently published in The Lancet Oncology.2
At the time of the analysis, the median duration of treatment in
the trial was 8.3 months with CABOMETYX versus 4.4 months with
everolimus. The most frequent adverse events regardless of
causality were diarrhea, fatigue, decreased appetite and
hypertension for CABOMETYX and fatigue, anemia, decreased appetite
and cough for everolimus. Dose reductions occurred for 62 percent
and 25 percent of patients, respectively. Discontinuation rate due
to an adverse event not related to disease progression was 12
percent with CABOMETYX and 11 percent with everolimus.
About Advanced Renal Cell Carcinoma
Renal cell carcinoma (RCC) represents 2-3 percent of all
cancers3, with the highest incidence occurring in Western
countries. Generally, during the last two decades until recently,
there has been an annual increase of about 2 percent in incidence
both worldwide and in Europe, though in Denmark and Sweden a
continuing decrease has been observed.4 In 2012, there were
approximately 84,400 new cases of RCC and 34,700 kidney cancer
related deaths within the European Union.5 In Europe, overall
mortality rates for RCC have increased up until the early 1990s,
with rates generally stabilizing or declining thereafter.6 There
has been a decrease in mortality since the 1980s in Scandinavian
countries and since the early 1990s in France, Germany, Austria,
the Netherlands, and Italy. However, in some European countries
(Croatia, Estonia, Greece, Ireland, Slovakia), mortality rates
still show an upward trend with increasing rates. 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 VEGFR inhibitors.8,9
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 with the potential to improve care and outcomes for
people with cancer. Since its founding in 1994, three medicines
discovered at Exelixis have progressed through clinical development
to receive regulatory approval. Currently, Exelixis is focused on
advancing cabozantinib, an inhibitor of multiple tyrosine kinases
including MET, AXL and VEGF receptors, which has shown clinical
anti-tumor activity in more than 20 forms of cancer and is the
subject of a broad clinical development program. Two separate
formulations of cabozantinib have received regulatory approval to
treat certain forms of kidney and thyroid cancer and are marketed
for those purposes as CABOMETYX™ tablets (U.S. and EU) and
COMETRIQ® capsules (U.S. and EU), respectively. Another
Exelixis-discovered compound, COTELLIC™ (cobimetinib), a selective
inhibitor of MEK, has been approved in major territories including
the United States and European Union, and is being evaluated for
further potential indications by Roche and Genentech (a member of
the Roche Group) under a collaboration with Exelixis. For more
information on 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’
further examination of the use of CABOMETYX in earlier lines of
therapy and in other difficult-to-treat cancers;
Exelixis' commitment to the discovery, development and
commercialization of new medicines with the potential to improve
care and outcomes for people with cancer; Exelixis’ focus on
advancing cabozantinib; and the continued development of
cobimetinib. Words such as “look forward,” “committed,” “focused,”
“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 degree of
market acceptance of CABOMETYX and the availability of coverage and
reimbursement for CABOMETYX; the risk that unanticipated
developments could adversely affect the commercialization of
CABOMETYX; Exelixis’ dependence on its relationship
with Ipsen, including, the level of Ipsen’s investment in the
resources necessary to successfully commercialize cabozantinib in
the territories where it is approved; risks and uncertainties
related to regulatory review and approval processes and Exelixis’
compliance with applicable legal and regulatory requirements;
Exelixis’ ability to conduct clinical trials of cabozantinib
sufficient to achieve a positive completion; risks related to the
potential failure of cabozantinib to demonstrate safety and
efficacy in clinical testing; 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 August 3,
2016, 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 TK, Escudier B, Powles T, et al. Cabozantinib versus
Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;
373(19):1814-1823.
2. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus
everolimus in advanced renal cell carcinoma (METEOR): final results
from a randomised, open-label, phase 3 trial. Lancet Onc. 2016 Jun
5; S1470-2045(16)30107-3.
3. European Network of Cancer Registries. Eurocim version 4.0.
European incidence database V2.3, 730 entity dictionary (2001),
Lyon, 2001.
4. Lindblad P. Epidemiology of renal cell carcinoma. Scand J
Surg 2004;93(2):88-96
http://www.ncbi.nlm.nih.gov/pubmed/15285559
5. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al.
Cancer incidence and mortality patterns in Europe: estimates for 40
countries in 2012. Eur J Cancer 2013 Apr;49(6):1374-403.
http://www.ncbi.nlm.nih.gov/pubmed/23485231
6. Levi F, Ferlay J, Galeone C, et al. The changing pattern of
kidney cancer incidence and mortality in Europe. BJU Int 2008
Apr;101(8):949-58 http://www.ncbi.nlm.nih.gov/pubmed/18241251
7. Harshman, L.C. and Choueiri, T.K., 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. 2015 Sep 14. doi:10.1038/onc.2015.343. [Epub ahead of
print].
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 SJ, 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)
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Affairsshubbard@exelixis.comorMedia:Lindsay Treadway, (650)
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