- IRC Confirms Cabozantinib Significantly
Improved Progression-Free Survival Compared to Sunitinib -
- U.S. Regulatory Submission Remains on
Track for Q3’17 -
Exelixis, Inc. (NASDAQ:EXEL) announced today that the analysis
of the review by a blinded independent radiology review committee
(IRC) has confirmed the primary efficacy endpoint results of
investigator-assessed progression-free survival (PFS) from the
CABOSUN randomized phase 2 trial of cabozantinib as compared with
sunitinib 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
(IMDC). Per the IRC analysis, cabozantinib demonstrated a
clinically meaningful and statistically significant reduction in
the rate of disease progression or death as measured by PFS.
Exelixis remains on target to complete a supplemental New Drug
Application (sNDA) for cabozantinib as a treatment of first-line
advanced renal cell carcinoma in the third quarter of 2017.
CABOSUN was conducted by The Alliance for Clinical
Trials in Oncology as part of Exelixis’ agreement with the
National Cancer Institute’s Cancer Therapy Evaluation Program
(NCI-CTEP). Exelixis and the Alliance cooperative group plan to
submit these results for presentation at an upcoming international
medical meeting.
“We are very pleased that CABOSUN’s primary endpoint of a
statistically significant improvement of progression-free survival
has been confirmed by the independent radiology review committee,”
said Michael M. Morrissey, Ph.D., President and Chief Executive
Officer of Exelixis. “We continue in our focused efforts to
complete the regulatory filing of cabozantinib for the treatment of
patients with previously untreated advanced renal cell carcinoma
and are on track to submit a supplemental New Drug Application in
the third quarter of this year. Patients in the first-line setting
with either intermediate- or poor-risk disease progress rapidly
with sunitinib, a current standard of care, highlighting a clear
need for new options that provide improved clinical benefit in this
difficult to treat patient population.”
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. CABOSUN was conducted by The Alliance for
Clinical Trials in Oncology as part of Exelixis’ collaboration with
the NCI-CTEP. These results were first presented by Dr. Toni
Choueiri at the meeting of the European Society for Medical
Oncology (ESMO) 2016, and published in the Journal of Clinical
Oncology (Choueiri, JCO, 2016).1
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, four weeks on followed by two 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.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.8,9
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 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.
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
MET, AXL and VEGF receptors: CABOMETYX™ tablets approved for
previously treated advanced kidney cancer and COMETRIQ® capsules
approved for progressive, metastatic medullary thyroid cancer. The
third product, COTELLIC®, is a formulation of cobimetinib, a
selective 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 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: the timing of
completion and submission of an sNDA for cabozantinib in first-line
RCC; the timing of submission of CABOSUN results for presentation
ta an upcoming international medical meeting; the potential of
cabozantinib to benefit patients with advanced RCC as a first-line
therapy; 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 “remains,” “will,” “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; Exelixis’ ability and the ability
of its collaborators to complete and submit regulatory filings;
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’
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 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.
Exelixis, the Exelixis logo, COMETRIQ and
COTELLIC are registered U.S. trademarks, and CABOMETYX is a U.S.
trademark.
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.K., Renal cell carcinoma. BMJ. 2014;
349:g4797. 5. Ko, J. J., Choueiri, T.K., 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.C. and Choueiri, T.K., Targeting the
hepatocyte growth factor/c-Met signaling pathway in renal cell
carcinoma. Cancer J. 2013; 19(4):316-23. 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):13373-8. 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(21):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 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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Investors:Exelixis, Inc.Susan Hubbard, 650-837-8194EVP,
Public Affairs and Investor
Relationsshubbard@exelixis.comorMedia:Exelixis, Inc.Lindsay
Treadway, 650-837-7522Director, Public Affairs andAdvocacy
Relationsltreadway@exelixis.com
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