– 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
–
Exelixis, 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 three weeks).
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 patients.”
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 receptor inhibitors.5,6
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 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 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:g4797.3 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; 19:316-323.5 Rankin, et
al. Direct regulation of GAS6/AXL signaling by HIF promotes renal
metastasis through SRC and MET. Proc Natl Acad Sci USA. 2014;
111:13373-13378.6 Zhou, L., Liu, X-D., Sun, M., et al. Targeting
MET and AXL overcomes resistance to sunitinib therapy in renal cell
carcinoma. Oncogene. 2016; 35:2687-2697.7 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;
19:5902–5912.8 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; 54:4233-4237.9
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.
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version on businesswire.com: https://www.businesswire.com/news/home/20181022005259/en/
Investors:Susan HubbardEVP, Public Affairs and Investor
RelationsExelixis, Inc.(650)
837-8194shubbard@exelixis.comorMedia:Lindsay TreadwaySenior
Director, Public Affairs and Advocacy RelationsExelixis, Inc.(650)
837-7522ltreadway@exelixis.com
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