– Cabozantinib met the primary endpoint of
improving progression-free survival as compared to sunitinib,
decreasing the rate of disease progression or death by 31 percent
–
– Objective response rate significantly
improved: 46 percent for cabozantinib versus 18 percent for
sunitinib –
– Exelixis to host investor and media
webcast from Copenhagen to discuss the data on Monday, October 10
–
Exelixis, Inc. (NASDAQ:EXEL) today announced detailed results
from the CABOSUN randomized phase 2 trial of cabozantinib 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).
Principal investigator Toni K. Choueiri, M.D. will present detailed
data from late-breaking CABOSUN abstract [#LBA30_PR] today in the
Presidential Symposium 3 session, starting at 16:30 CEST (local
Copenhagen time) / 10:30 a.m. EDT / 7:30 a.m. PDT at the European
Society for Medical Oncology (ESMO) 2016, which is being held
October 7 – 11, 2016 in Copenhagen.
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).
In CABOSUN, with a median follow-up of 20.8 months, cabozantinib
demonstrated a clinically meaningful and statistically significant
31 percent reduction in the rate of disease progression or death
[HR 0.69, 95% CI (0.48-0.99), one-sided P=0.012]. The median
progression-free survival (PFS) for cabozantinib was 8.2 months
versus 5.6 months for sunitinib, corresponding to a 2.6 months (46
percent) improvement favoring cabozantinib over sunitinib. PFS
benefits were independent of IMDC risk group (intermediate or
poor risk) and presence or absence of bone metastases at baseline.
The results for sunitinib were in line with a previously published
retrospective analysis of 1,174 intermediate- and poor-risk RCC
patients from the IMDC database, which documented a median PFS of
5.6 months with a first-line targeted therapy, mainly sunitinib, in
this patient population.1
Objective response rate (ORR) was also significantly improved,
at 46 percent (95% CI 34% – 57%) for cabozantinib versus 18 percent
(95% CI 10% to 28%) for sunitinib. With a median follow up of 22.8
months, median overall survival was 30.3 months for cabozantinib
versus 21.8 months for sunitinib [HR 0.80, 95% CI (0.50 -
1.26)].
“The results presented today support the potential of
cabozantinib to become a new therapeutic option for previously
untreated patients following their diagnosis with advanced kidney
cancer,” said Toni K. Choueiri, M.D., Director, Lank Center for
Genitourinary Oncology, Dana-Farber Cancer Institute and chair of
the CABOSUN study. “Not only has cabozantinib surpassed sunitinib,
the current standard of care, in progression-free survival and
objective response rate, cabozantinib’s effects on progression-free
survival were also consistently favorable across patient
stratification subgroups including IMDC intermediate versus
poor-risk groups and presence or absence of bone metastases.”
“We at the Alliance for Clinical Trials in Oncology are pleased
that CABOSUN has successfully demonstrated that cabozantinib has
the potential to benefit patients with advanced renal cell
carcinoma as a first-line therapy,” said Michael J. Morris, M.D.,
Associate Member at Memorial Sloan Kettering Cancer Center, and
Chair of the Alliance Genitourinary Committee. “We are grateful to
everyone who has participated in the trial, especially the
physicians, patients and their families.”
Based on these results, Exelixis plans to submit a Supplemental
New Drug Application (sNDA) for cabozantinib as a treatment of
first-line advanced renal cell carcinoma, and is working with the
Alliance to transfer the complete CABOSUN clinical database to
Exelixis.
“The past year has seen a tremendous level of progress in the
treatment of kidney cancer, and we are excited to be at the
forefront of bringing these advancements to patients,” said Michael
M. Morrissey, Ph.D., president and chief executive officer of
Exelixis. “Patients in the first-line setting with either
intermediate- or poor-risk disease progress rapidly with sunitinib,
a current standard of care; therefore, there is a clear need for
new options that provide improved clinical benefit in this
difficult to treat patient population. To that end, based on the
CABOSUN results, we are planning to submit a supplemental New Drug
Application in the United States for cabozantinib as a first-line
treatment for advanced renal cell carcinoma.”
CABOSUN enrolled 157 patients with previously untreated advanced
RCC: 80.9 percent of patients were intermediate risk per IMDC
criteria and 19.1 percent were poor risk, 36.3 percent of patients
had bone metastases, 46 percent of patients had ECOG Performance
Status (PS) 0, 41 percent had ECOG PS 1, and 13 percent had ECOG PS
2. All patients were included in the efficacy analyses that
followed the intent-to-treat principle. Tumor assessments were
performed by the investigators following RECIST criteria. At the
time of the analysis of the primary endpoint of PFS, the median
duration of treatment in CABOSUN was 6.9 months with cabozantinib
and 2.8 months with sunitinib; 13 patients continued on
cabozantinib treatment versus 2 patients on sunitinib treatment.
Dose reductions occurred for 58 percent and 49 percent of patients,
respectively. Discontinuation rate due to an adverse event was 20
percent with cabozantinib and 21 percent with sunitinib.
One hundred and fifty patients were evaluable for safety.
Ninety-nine percent of patients on both arms experienced at least
one adverse event. The most common all causality grade 3 or 4
adverse events observed in more than 5 percent of patients were
hypertension (28 percent), diarrhea (10 percent), palmar-plantar
erythrodysesthesia (8 percent), and fatigue (6 percent) in the
cabozantinib arm, and hypertension (22 percent), fatigue (15
percent), diarrhea and thrombocytopenia (both 11 percent), and oral
mucositis (6 percent) in the sunitinib arm. Treatment-related grade
5 events occurred in three patients in the cabozantinib arm (acute
kidney injury, sepsis and jejunal perforation) and two patients in
the sunitinib arm (sepsis and vascular disorder).
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. CABOSUN is being
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).
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). 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.
Webcast for the Financial Community and Media
Exelixis and its partner Ipsen will jointly host a live webcast
today, Monday, October 10. The webcast will begin at 19:00 CEST
(local Copenhagen time) / 1:00 p.m. EDT / 10:00 a.m. PDT. During
the webcast, Exelixis and Ipsen management and invited guest
speakers will review and provide context of the results from the
CABOSUN study, along with the other data sets on cabozantinib
presented at the conference.
To access the webcast link, log onto www.exelixis.com and
proceed to the Event Calendar page under Investors & Media.
Please connect to the company’s website at least 15 minutes prior
to the webcast to ensure adequate time for any software download
that may be required to view the program. To listen to an
audio-only version of the program by phone, please dial
855-299-5224 (domestic) or 631-267-4890 (international/toll dial)
and use passcode 234-026-024. An archived replay of the webcast
will be available on the Event Calendar page under Investors &
Media at www.exelixis.com after the event concludes.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2016 statistics cite kidney cancer
as among the top ten most commonly diagnosed forms of cancer among
both men and women in the U.S.2 Clear cell RCC is the most common
type of kidney cancer in adults.3 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.1 Approximately 30,000 patients in the U.S. and 68,000
globally require treatment.4
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.5,6 These proteins promote tumor
angiogenesis (blood vessel growth), growth, invasiveness and
metastasis.7-10 MET and AXL may provide escape pathways that drive
resistance to VEGF receptor inhibitors.6,7
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. 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.
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: the
presentation of detailed data from CABOSUN at ESMO; the potential
of cabozantinib to become a new therapeutic option for previously
untreated patients following their diagnosis with advanced kidney
cancer; the potential of cabozantinib to benefit patients with
advanced RCC as a first-line therapy; Exelixis’ plans to submit a
sNDA in the United States for cabozantinib as a treatment for
first-line advanced RCC; 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 “will,” “potential,”
“plans,” “committed,” “focused,” 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 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; risks and uncertainties related to
regulatory review and approval processes and Exelixis’ compliance
with applicable legal and regulatory requirements; 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; 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
- 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.) 110, 1917–1922.
- American Cancer Society. Cancer Facts
& Figures 2016. Atlanta: American Cancer Society; 2016.
- Jonasch E., Gao J., Rathmell W.K.,
Renal cell carcinoma. BMJ. 2014; 349:g4797.
- 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. 2013; 19(4):316-23.
- 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. 2015 Sep 14.
doi:10.1038/onc.2015.343. [Epub ahead of print].
- 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 Urol. 1997;79:681-687.
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Investors:Exelixis, Inc.Susan Hubbard,
650-837-8194Investor Relations & Public
Affairsshubbard@exelixis.comorMedia:Exelixis, Inc.Lindsay
Treadway, 650-837-7522Public Affairs & Advocacy
Relationsltreadway@exelixis.com
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