– Combination of cabozantinib and atezolizumab is well
tolerated and shows promising anti-tumor activity –
– Safety and efficacy data support 18 expansion cohorts evaluating
the combination in 12 different tumor types –
ALAMEDA, Calif.--(BUSINESS WIRE)--Oct. 22, 2018--
Inc. (NASDAQ:EXEL) today announced results from the dose-escalation
stage of the phase 1b COSMIC-021 study of cabozantinib in combination
with atezolizumab in previously untreated advanced renal cell carcinoma
(RCC). The primary objective of the dose-escalation stage of the trial
was to determine the recommended dose of cabozantinib in combination
with the standard dose of atezolizumab for the expansion stage of the
trial. The findings demonstrate encouraging clinical activity for the
combination, supporting further evaluation of the 40 mg dose of
cabozantinib in combination with the standard dose of atezolizumab in
the ongoing expansion phase of the trial. The findings were presented
during a poster session (abstract 872P) on Monday, October 22 at the
European Society for Medical Oncology (ESMO) 2018 Congress, which is
being held October 19-23, 2018 in Munich, Germany.
Twelve patients with previously untreated advanced RCC including ten
patients with clear cell RCC and two patients with non-clear cell RCC
were treated in the dose-escalation stage, with six patients at each
cabozantinib dose level — 40 mg or 60 mg daily — in combination with the
standard dosing regimen of atezolizumab (1,200 mg infusion once every
As of the August 21, 2018 data cut-off, all patients remained on
treatment. Median follow-up was 33.4 weeks. Eight of the ten (80
percent) clear cell RCC patients achieved a response per RECIST 1.1.
Among all 12 patients enrolled, including the 2 non-clear cell RCC
patients, the response rate was 67 percent. The disease control rate
(ORR plus stable disease) for all 12 patients was 100 percent.
No dose-limiting toxicities or serious adverse events were noted at
either cabozantinib dose. Dose reductions and higher grade AEs were less
frequent with the 40 mg cabozantinib dosing cohort. Grade 3 adverse
events (83 percent of patients) in the 40 mg cabozantinib dose cohort
included hypertension (50 percent), hypophosphatemia (17 percent),
hyperglycemia (17 percent), gamma glutamyltransferase increased (17
percent) and muscular weakness (17 percent). Grade 3 adverse events (100
percent of patients) in the 60 mg cabozantinib dose cohort included
diarrhea (33 percent), hypertension (33 percent), aspartate
aminotransferase increased (17 percent), alanine aminotransferase
increased (17 percent), lymphopenia (17 percent), hypophosphatemia (17
percent) and lipase increased (17 percent). No Grade 4 or 5 adverse
events were observed.
“These early stage results demonstrate that the combination of
cabozantinib and atezolizumab was well tolerated and showed promising
anti-tumor activity in advanced kidney cancer,” said Sumanta Kumar Pal,
M.D., associate clinical professor, Department of Medical Oncology and
Therapeutics Research, co-director, Kidney Cancer Program, City of Hope.
“We look forward to continuing to advance this trial to understand
whether this combination may benefit patients with multiple tumor types.”
“As we explore cabozantinib in combination with a variety of immune
checkpoint inhibitors in a broad spectrum of tumor types, we are pleased
with the initial results in the dose-escalation phase of COSMIC-021,”
said Gisela Schwab, M.D., President, Product Development and Medical
Affairs and Chief Medical Officer, Exelixis. “This combination is being
studied across 12 different tumor types in the expansion phase, and we
are excited to see how it may improve outcomes for this range of
As previously announced, the cabozantinib starting dose for the
expansion phase is 40 mg. The expansion phase includes multiple solid
tumor types, including RCC. More information about this trial is
available at ClinicalTrials.gov.
Please see Important Safety Information below and full U.S. prescribing
information at https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About the COSMIC-021 Study
COSMIC-021 is a multicenter, phase 1b, open-label study that is divided
into two parts: a dose-escalation phase and an expansion cohort phase.
The dose-escalation phase was designed to enroll patients either with
advanced RCC with or without prior systemic therapy or with inoperable,
locally advanced, metastatic or recurrent UC (including renal, pelvis,
ureter, urinary bladder and urethra) after prior platinum-based therapy.
Ultimately, all patients enrolled in this stage of the trial were
patients with advanced RCC. The dose-escalation phase of the study
determined the optimal dose of cabozantinib to be 40 mg daily when given
in combination with atezolizumab (1200 mg infusion once every 3 weeks).
In the expansion phase, the trial is enrolling 18 expansion cohorts in
12 tumor types: RCC, urothelial carcinoma (UC), non-small cell lung
cancer (NSCLC), castration-resistant prostate cancer, triple-negative
breast cancer, epithelial ovarian cancer, endometrial cancer,
hepatocellular carcinoma (HCC), gastric or gastroesophageal junction
adenocarcinoma, colorectal adenocarcinoma, head and neck cancer, and
differentiated thyroid cancer. Up to a total of 1,000 patients may
enroll in this phase of the trial: each expansion cohort will initially
enroll approximately 30 patients; up to 80 patients may enroll in up to
eight of those cohorts, including the cohorts with UC or NSCLC patients
who have been previously treated with an immune checkpoint inhibitor;
and in two exploratory cohorts, approximately 30 patients in each cohort
will be treated with cabozantinib as a single-agent.
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.1 Clear cell RCC is the most common type
of kidney cancer in adults.2 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, and
an estimated 14,000 patients in the U.S. each year are in need of a
first-line treatment for advanced kidney cancer. 3
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.4,5 These proteins promote tumor angiogenesis
(blood vessel growth), growth, invasiveness and metastasis.6,7,8,9 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.
The combination of cabozantinib and atezolizumab is not indicated for
previously untreated advanced RCC.
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,
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Forward-Looking Statement Disclaimer
This press release contains forward-looking statements, including,
without limitation, statements related to: the further evaluation of the
combination of cabozantinib with the standard dose of atezolizumab as
part of the expansion phase of COSMIC-021; the potential of the
combination of cabozantinib and atezolizumab to benefit patients with
multiple tumor types; 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: risks and uncertainties related to
regulatory review and approval processes and Exelixis’ compliance with
applicable legal and regulatory requirements; the potential failure of
the combination of cabozantinib and atezolizumab to demonstrate safety
and/or efficacy in COSMIC-021; uncertainties inherent in the product
development process; the costs of conducting clinical trials, including
the ability or willingness of Exelixis’ collaboration partners to invest
in the resources necessary to complete the trials, as well as Exelixis’
dependence on third-party vendors for the development, manufacture and
supply of cabozantinib; Exelixis’ ability to protect its intellectual
property rights; market competition; changes in economic and business
conditions; and other factors affecting Exelixis and its development
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 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.
2 Jonasch, E., Gao, J.,
Rathmell, W. Renal cell carcinoma. BMJ. 2014; 349:g4797.
Decision Resources Report: Renal Cell Carcinoma. October 2014 (internal
data on file).
4 Harshman, L., and Choueiri, T.
Targeting the hepatocyte growth factor/c-Met signaling pathway in renal
cell carcinoma. Cancer J. 2013; 19:316-323.
Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF promotes
renal metastasis through SRC and MET. Proc Natl Acad Sci USA.
6 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.
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;
8 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;
9 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/20181022005259/en/
Source: Exelixis, Inc.
EVP, Public Affairs
and Investor Relations
Senior Director, Public Affairs and Advocacy