– 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 –
ALAMEDA, Calif.--(BUSINESS WIRE)--Oct. 20, 2018--
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
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
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
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
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.
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;
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.
View source version on businesswire.com: https://www.businesswire.com/news/home/20181020005006/en/
Source: Exelixis, Inc.
EVP, Public Affairs and Investor
Lindsay Treadway, 650-837-7522
Director, Public Affairs and Advocacy Relations