– Cabozantinib was associated with improved
overall survival and progression-free survival irrespective of
PD-L1 expression in CABOSUN and METEOR trials –
– Cabozantinib also demonstrated activity in
patients previously treated with immune checkpoint inhibitors
–
– Findings presented this week at ESMO 2018
–
Exelixis, Inc. (NASDAQ:EXEL) today announced results from two
analyses evaluating the effect of PD-L1 expression or prior
treatment with immune checkpoint inhibitors on the efficacy of
cabozantinib in patients with advanced renal cell carcinoma (RCC).
The findings are being presented this week at the European Society
for Medical Oncology (ESMO) 2018 Congress being held October 19–23
in Munich, Germany.
An analysis of data from the CABOSUN and METEOR trials
demonstrated that cabozantinib improved clinical outcomes
regardless of PD-L1 status in patients with advanced RCC, relative
to sunitinib or everolimus, the respective comparator arms for each
trial. The late-breaking abstract [LBA 34] is being presented today
in the Genitourinary Tumors, Non Prostate poster discussion session
starting at 2:45 p.m. CEST (local Munich time).
Tumor tissue from 110 patients in the CABOSUN trial and 306
patients in the METEOR trial were evaluated to determine whether
PD-L1 expression (≥1% of tumor cells) predicted outcomes or
response to treatment. The findings showed that PD-L1 expression
was associated with shorter median progression-free survival (PFS)
and overall survival (OS) in both METEOR and CABOSUN. Treatment
with cabozantinib, however, improved PFS and OS compared with
everolimus (METEOR) and sunitinib (CABOSUN) in both PD-L1 positive
and PD-L1 negative patients.
“As cabozantinib has become a new standard of care for the
treatment of advanced kidney cancer, there is great interest in
identifying biomarkers to help select for patients who would
potentially derive the most clinical benefit,” said Toni Choueiri,
M.D., Director, Lank Center for Genitourinary Oncology, Dana-Farber
Cancer Institute, and lead investigator. “While evidence suggests
that patients who are negative for PD-L1 have less benefit with
immune checkpoint inhibitors, this analysis demonstrated that
cabozantinib may be an effective treatment option regardless of
PD-L1 status for patients with advanced kidney cancer.”
An additional analysis evaluating the activity of cabozantinib
in 69 patients with advanced RCC who progressed on immune
checkpoint inhibitors [abstract 879P] will be presented by lead
investigator Bradley McGregor, M.D., Dana-Farber Cancer Institute,
at ESMO on Monday, October 22 in a poster display session at 12:45
p.m. CEST. This retrospective analysis found that cabozantinib was
active in patients previously treated with immune checkpoint
inhibitors, either alone or in combination with anti-VEGF or other
therapies. At a median follow-up of 12 months, objective response
rate was 33 percent, disease control rate was 79 percent and the
one-year overall survival rate was 53 percent.
“With a growing number of options available for advanced kidney
cancer, physicians need to consider multiple factors when selecting
and sequencing treatments for patients,” said Michael M. Morrissey,
Ph.D., President and Chief Executive Officer of Exelixis. “The
findings from these additional analyses demonstrate the potential
benefit with cabozantinib for patients regardless of PD-L1
expression as well as after treatment with immune checkpoint
inhibitors, reinforcing its role as the TKI of choice for advanced
kidney cancer.”
About the CABOSUN Study
On May 23, 2016, Exelixis announced that the
phase 2 CABOSUN study 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. The
CABOSUN study was conducted by The Alliance for Clinical
Trials in Oncology and was sponsored by the National Cancer
Institute-Cancer Therapy Evaluation Program (NCI-CTEP) under
the Cooperative Research and Development Agreement
with Exelixis for the development of cabozantinib. These
results were first presented by Dr. Toni Choueiri at
the European Society for Medical Oncology (ESMO)
2016 Congress and published in the Journal of Clinical
Oncology (Choueiri, JCO, 2016).1 In June 2017, a
blinded independent radiology review committee (IRC) confirmed that
cabozantinib provided a clinically meaningful and statistically
significant improvement in the primary efficacy endpoint of
investigator-assessed PFS. Results from the IRC review were
presented by Dr. Toni Choueiri at the ESMO
2017 Congress.
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, objective response rate and safety. 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.
About the METEOR Study
METEOR was an open-label, event-driven trial of 658 patients
with advanced RCC who had failed at least one prior VEGFR TKI
therapy. The primary endpoint was PFS in the first 375 patients
treated. 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 of significantly improving PFS
and significantly improved the objective response rate compared
with everolimus. These data were presented at ESMO 2015 and
published in The New England Journal of Medicine.3 CABOMETYX also
demonstrated a statistically significant and clinically meaningful
increase in OS in the METEOR trial. Cabozantinib 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.4
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2018 statistics cite kidney cancer
as among the top ten most commonly diagnosed forms of cancer among
both men and women in the U.S.5 Clear cell RCC is the most
common type of kidney cancer in adults.6 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. 7
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.8,9 These proteins promote tumor
angiogenesis (blood vessel growth), growth, invasiveness and
metastasis.10,11,12,13 MET and AXL may provide escape pathways
that drive resistance to VEGF receptor inhibitors.9,10
About CABOMETYX® (cabozantinib)
CABOMETYX tablets are approved in the United States for the
treatment of patients with advanced RCC. CABOMETYX tablets are also
approved in the European Union, Norway, Iceland, Australia,
Switzerland, South Korea and Canada for the treatment of advanced
RCC in adults who have received prior VEGF-targeted therapy, and in
the European Union for previously untreated intermediate- or
poor-risk advanced RCC. In March 2017, the FDA granted orphan drug
designation to cabozantinib for the treatment of advanced HCC. In
May 2018, the FDA accepted Exelixis’ supplemental New Drug
Application for CABOMETYX as a treatment for patients with
previously treated HCC and assigned it a Prescription Drug User Fee
Act action date of January 14, 2019. On March 28, 2018, Ipsen
announced that the European Medicines Agency validated its
application for a new indication for cabozantinib as a treatment
for previously treated advanced HCC in the European Union; on
September 20, 2018 the CHMP provided a positive opinion for
CABOMETYX as a monotherapy for the treatment of HCC in adults who
have been previously treated with sorafenib. In 2016, Exelixis
granted Ipsen exclusive rights for the commercialization and
further clinical development of cabozantinib outside of the United
States and Japan. In 2017, Exelixis granted exclusive rights to
Takeda Pharmaceutical Company Limited for the commercialization and
further clinical development of cabozantinib for all future
indications in Japan.
U.S. Important Safety Information
- Hemorrhage: Severe and fatal
hemorrhages have occurred with CABOMETYX. In two RCC studies, the
incidence of Grade ≥ 3 hemorrhagic events was 3% in
CABOMETYX-treated patients. Do not administer CABOMETYX to patients
that have or are at risk for severe hemorrhage.
- Gastrointestinal (GI) Perforations
and Fistulas: In RCC studies, fistulas were reported in 1% of
CABOMETYX-treated patients. Fatal perforations occurred in patients
treated with CABOMETYX. In RCC studies, gastrointestinal (GI)
perforations were reported in 1% of CABOMETYX-treated patients.
Monitor patients for symptoms of fistulas and perforations,
including abscess and sepsis. Discontinue CABOMETYX in patients who
experience a fistula which cannot be appropriately managed or a GI
perforation.
- Thrombotic Events: CABOMETYX
treatment results in an increased incidence of thrombotic events.
In RCC studies, venous thromboembolism occurred in 9% (including 5%
pulmonary embolism) and arterial thromboembolism occurred in 1% of
CABOMETYX-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, including hypertensive crisis.
In RCC studies, hypertension was reported in 44% (18% Grade
≥ 3) of CABOMETYX-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: In RCC studies,
diarrhea occurred in 74% of patients treated with CABOMETYX.
Grade 3 diarrhea occurred in 11% of patients treated with
CABOMETYX. 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.
- Palmar-Plantar Erythrodysesthesia
(PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE)
occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE
occurred in 8% of patients treated with CABOMETYX. Withhold
CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade
3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced
dose.
- Reversible Posterior
Leukoencephalopathy Syndrome (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 may be
associated with CABOMETYX. Advise pregnant women of the potential
risk to a fetus. Advise females of reproductive potential to use
effective contraception during CABOMETYX treatment and for 4 months
after the last dose.
- Adverse Reactions: The most
commonly reported (≥25%) adverse reactions are: diarrhea, fatigue,
nausea, decreased appetite, hypertension, PPE, weight decreased,
vomiting, dysgeusia, and stomatitis.
- Strong CYP3A4 Inhibitors: If
concomitant use with strong CYP3A4 inhibitors cannot be avoided,
reduce the CABOMETYX dosage.
- Strong CYP3A4 Inducers: If
concomitant use with strong CYP3A4 inducers cannot be avoided,
increase the CABOMETYX dosage.
- Lactation: Advise women not to
breastfeed while taking CABOMETYX and for 4 months after the final
dose.
- Hepatic Impairment: In patients
with mild to moderate hepatic impairment, reduce the CABOMETYX
dosage. CABOMETYX is not recommended for use in patients with
severe hepatic impairment.
Please see accompanying full Prescribing Information
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About Exelixis
Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially
successful, oncology-focused biotechnology company that strives to
accelerate the discovery, development and commercialization of new
medicines for difficult-to-treat cancers. Following early work in
model genetic systems, we established a broad drug discovery and
development platform that has served as the foundation for our
continued efforts to bring new cancer therapies to patients in
need. We discovered our three commercially available products,
CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib) and COTELLIC®
(cobimetinib), and have entered into partnerships with leading
pharmaceutical companies to bring these important medicines to
patients worldwide. Supported by revenues from our marketed
products and collaborations, we are committed to prudently
reinvesting in our business to maximize the potential of our
pipeline. We are supplementing our existing therapeutic assets with
targeted business development activities and internal drug
discovery - all to deliver the next generation of Exelixis
medicines and help patients recover stronger and live longer. In
July 2018, Exelixis was added to the Standard & Poor’s
(S&P) MidCap 400 index, which measures the performance of
profitable mid-sized companies. For more information about
Exelixis, please visit www.exelixis.com,
follow @ExelixisInc on Twitter or like Exelixis,
Inc. on Facebook.
Forward-Looking Statement Disclaimer
This press release contains forward-looking statements,
including, without limitation, statements related to: the potential
of cabozantinib to be an effective treatment option for patients
with advanced RCC, regardless of their PD-L1 expression, as well as
after treatment with immune checkpoint inhibitors; and Exelixis’
plans to reinvest in its business to maximize the potential of the
company’s pipeline, including through targeted business development
activities and internal drug discovery. Any statements that refer
to expectations, projections or other characterizations of future
events or circumstances are forward-looking statements and 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 sufficient
coverage and adequate reimbursement for this product; Exelixis’
ability to invest in the resources necessary to successfully
commercialize its compounds in the territories where they are
approved and to execute its commercial strategy; Exelixis’
continuing compliance with applicable legal and regulatory
requirements; the potential failure of cabozantinib to continue to
demonstrate improved outcomes for patients who participated in
METEOR and CABOSUN; Exelixis’ dependence on third-party vendors for
the development, manufacture and supply of cabozantinib; Exelixis’
ability to protect its intellectual property rights; market
competition, including the potential for competitors to obtain
approval for generic versions of Exelixis’ marketed products;
changes in economic and business conditions; and other factors
affecting Exelixis and its commercial programs discussed
under the caption “Risk Factors” in Exelixis’ Quarterly Report on
Form 10-Q filed with the Securities and Exchange
Commission (SEC) on August 1, 2018, and in Exelixis’
future filings with the SEC. All forward-looking statements in
this press release are based on information available
to Exelixis as of the date of this press
release, and Exelixis undertakes no obligation to update
or revise any forward-looking statements contained herein.
Exelixis, the Exelixis logo, CABOMETYX,
COMETRIQ and COTELLIC are registered U.S. trademarks.
_________________________________________
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. Am J Clin Oncol. 2016;
35:591-597.
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. Am J Clin Oncol. 2009; 27:5794-5799.
3 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.
4 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.
5 American Cancer Society: Cancer Facts
and Figures 2018. Available
at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf.
Accessed October 2018.
6 Jonasch, E., Gao, J., Rathmell, W. Renal
cell carcinoma. BMJ. 2014; 349:g4797.
7 Decision Resources Report: Renal Cell
Carcinoma. October 2014 (internal data on file).
8 Harshman, L., and Choueiri, T. Targeting
the hepatocyte growth factor/c-Met signaling pathway in renal cell
carcinoma. Cancer J. 2013; 19:316-323.
9 Rankin, et al. Direct regulation of
GAS6/AXL signaling by HIF promotes renal metastasis through SRC and
MET. Proc Natl Acad Sci USA. 2014; 111:13373-13378.
10 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.
11 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;
19:5902–5912.
12 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.
13 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 Contact:Susan Hubbard,
650-837-8194EVP, Public Affairs and Investor
Relationsshubbard@exelixis.comorMedia Contact:Lindsay
Treadway, 650-837-7522Senior Director, Public Affairs and Advocacy
Relationsltreadway@exelixis.com
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