- IRC Confirms Cabozantinib Significantly Improved
Progression-Free Survival Compared to Sunitinib -
- U.S. Regulatory Submission Remains on Track for Q3’17 -
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Jun. 19, 2017--
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
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
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
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
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
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
Please see full Prescribing Information at https://cabometyx.com/downloads/cabometyxuspi.pdf.
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.
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.
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;
American Cancer Society. Cancer Facts & Figures 2017. Atlanta:
American Cancer Society; 2017.
Jonasch E., Gao J., Rathmell W.K., Renal cell carcinoma. BMJ. 2014;
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.
Decision Resources Report: Renal Cell Carcinoma. October 2014
(internal data on file).
Harshman, L.C. and Choueiri, T.K., Targeting the hepatocyte growth
factor/c-Met signaling pathway in renal cell carcinoma. Cancer J.
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.
Zhou L, Liu X-D, Sun M, et al. Targeting MET and AXL overcomes
resistance to sunitinib therapy in renal cell carcinoma. Oncogene.
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.
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.
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
View source version on businesswire.com: http://www.businesswire.com/news/home/20170619005351/en/
Source: Exelixis, Inc.
EVP, Public Affairs and Investor
Lindsay Treadway, 650-837-7522
Public Affairs and