− Recommended doses for ongoing expansion
cohorts and future potential trials identified for doublet and
triplet combinations based on encouraging tolerability, safety and
activity profile −
Exelixis, Inc. (NASDAQ:EXEL) today announced results from a
phase 1 trial of cabozantinib in combination with either nivolumab
or nivolumab plus ipilimumab in patients with refractory
genitourinary tumors. The primary endpoint of the trial is to
determine the dose limiting toxicity (DLT) and recommended phase 2
doses of the doublet and triplet combinations. The findings were
presented during a poster session (Abstract #293) on February 17 at
the 2017 Genitourinary Cancers Symposium, which is being held in
Orlando, Florida, February 16 – 18, 2017.
Between July 22, 2015 and December 31, 2016, 48 patients were
accrued with previously treated metastatic urothelial carcinoma
(mUC, n=19), urachal adenocarcinoma (n=4), squamous cell carcinoma
of the bladder or urethra (n=2), germ cell tumor (n=4),
castration-resistant prostate cancer (n=9), renal cell carcinoma
(n=4), trophoblastic tumor (n=1), sertoli cell tumor (n=1) or
penile squamous cell carcinoma (n=4) and treated in two parts. In
Part I, 30 patients were treated with the doublet combination of
cabozantinib and nivolumab at four dose levels. In Part II, 18
patients were treated with the triplet combination of cabozantinib,
nivolumab and ipilimumab at three dose levels.
Among the 43 patients who were evaluable for response, the
objective response rate (ORR) for all tumor types was 30 percent
(38 percent for the doublet dosing schedule and 18 percent for the
triplet dosing schedule), with a 7 percent complete response (CR)
rate and a 23 percent partial response (PR) rate. Stable disease
(SD) was reported in 56 percent of patients. The ORR for patients
with mUC was 38 percent, and 2 of 16 patients achieved a CR, while
2 patients with squamous cell carcinoma of the bladder had
objective responses (1 CR and 1 PR). In the mUC cohort, 15 of 16
patients had a CR, PR or SD as their best response.
Grade 3 adverse events (>5 percent of patients) observed in
the doublet combination included neutropenia (17 percent),
hypophosphatemia (13 percent), hypertension (10 percent), lipase
increase (7 percent), fatigue (7 percent), diarrhea (7 percent) and
dehydration (7 percent). Grade 3 adverse events (>5 percent of
patients) observed in the triplet combination included hypertension
(17 percent), hypophosphatemia (17 percent), fatigue (13 percent),
hyponatremia (13 percent), lipase increase (13 percent), nausea (13
percent) and rash (6 percent). There were limited numbers of grade
4 adverse events (10 percent including thrombocytopenia and lipase
increase in the doublet combination, and 6 percent (lipase
increase) in the triplet combination), and no grade 5 adverse
events observed in either part of the trial.
“There is a significant unmet need for treatment regimens that
can slow tumor progression in advanced, intractable cancers such as
metastatic urothelial carcinoma. The use of combination therapies
may be a strategy that could increase anti-tumor activity in these
patients,” said Andrea Apolo, M.D., Genitourinary Malignancies
Branch, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, the principal investigator of the
trial. “Previously reported data from Part I of the trial showed
that cabozantinib in combination with nivolumab provided an
encouraging objective response rate and tolerability profile across
a diverse range of genitourinary tumors. Data from Part II also
demonstrate that using cabozantinib with two immunotherapy agents
is well-tolerated with promising early activity. These results
support the further evaluation of both regimens in these tumor
types.”
The recommended doses for the ongoing expansion cohorts were
determined to be cabozantinib 40 mg daily plus nivolumab 3 mg/kg
once every 2 weeks for the doublet and cabozantinib 40 mg daily,
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4
doses, then nivolumab 3 mg/kg every 2 weeks for the triplet.
“These early clinical results generated by our collaborators at
the NCI-CTEP suggest that the combination of cabozantinib with
either nivolumab or nivolumab and ipilimumab in patients with
genitourinary malignancies is associated with an encouraging
tolerability, safety and activity profile,” said Michael M.
Morrissey, Ph.D., president and Chief Executive Officer of
Exelixis. “With these results in hand, we are committed to further
examining the potential of cabozantinib in combination with a
variety of immunotherapies to treat a broad range of genitourinary
and other cancers.”
About the Trial
The trial is sponsored by the U.S. National Cancer
Institute (NCI) through Cooperative Research and
Development Agreements between the NCI’s Cancer Therapy Evaluation
Program (CTEP), Division of Cancer Treatment and Diagnosis,
and both Bristol-Myers Squibb and Exelixis. Andrea Apolo, M.D., of
the NCI’s Genitourinary Malignancies Branch, is the principal
investigator. The trial is being conducted by the NCI and includes
centers from its Experimental Therapeutics Clinical Trials
Network.
The primary endpoint of the phase 1 trial is to determine the
dose limiting toxicity (DLT) and recommended phase 2 doses of the
doublet and triplet combinations. The secondary endpoint is
clinical response rate as assessed by RECIST 1.1. Part I of the
study included four dosing levels: cabozantinib 40 mg daily plus
nivolumab 1 mg/kg once every 2 weeks; cabozantinib 40 mg daily plus
nivolumab 3 mg/kg once every 2 weeks; cabozantinib 60 mg daily plus
nivolumab 1 mg/kg once every 2 weeks; and cabozantinib 60 mg daily
plus nivolumab 3 mg/kg once every 2 weeks.
Part II of the study included three dosing levels: cabozantinib
40 mg daily, nivolumab 1 mg/kg plus ipilimumab 1 mg/kg every 3
weeks for 4 doses, then nivolumab 1 mg/kg every 2 weeks;
cabozantinib 40 mg daily, nivolumab 3 mg/kg plus ipilimumab
1 mg/kg every 3 weeks for 4 doses, then nivolumab 3 mg/kg
every 2 weeks; and cabozantinib 60 mg daily, nivolumab 3 mg/kg plus
ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 3
mg/kg every 2 weeks.
Data from Part I of the study evaluating the combination of
cabozantinib with nivolumab in patients with previously treated
genitourinary tumors were presented by Dr. Apolo at the European
Society for Medical Oncology 2016 Congress. Expansion cohorts
assessing cabozantinib and nivolumab are currently being accrued
with bladder, renal and rare genitourinary cancer patients. Data
from these patients will be reported at a later date.
About Genitourinary Cancers
Genitourinary cancers are those that affect the urinary tract,
bladder, kidneys, ureter, prostate, testicles, penis or adrenal
glands — parts of the body involved in reproduction and excretion —
and include renal cell carcinoma and urothelial carcinoma.1
Kidney cancer is among the top ten most commonly diagnosed forms
of cancer among both men and women in the U.S., according to the
American Cancer Society’s 2016 statistics.2 Clear cell renal cell
carcinoma 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.2 Approximately 30,000 patients in
the U.S. and 68,000 globally require treatment.4
Prostate cancer is the second most common cause of cancer death
in men, behind only skin cancer.5 There is a high survival rate for
patients when prostate cancer is detected early, but once the
disease has spread to other parts of the body the five-year
survival rate is just 28 percent.6 Approximately 2,850,000 men were
living with prostate cancer in the U.S. in 2013,7 and 180,000 new
cases are diagnosed each year.5
Urothelial cancers encompass carcinomas of the bladder, ureter
and renal pelvis at a ratio of 50:3:1, respectively.8 Urothelial
carcinoma occurs mainly in older people, with 90 percent of
patients aged 55 or older.9 Bladder cancer is the fourth most
common cancer in men and accounts for about five percent of all new
cases of cancer in the U.S. each year.9 In 2013, an estimated
587,426 people were living with bladder cancer in the U.S.10
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. On
December 21, 2016, this agreement was amended to include
commercialization rights for Ipsen in Canada. On January 30, 2017,
Exelixis and Takeda Pharmaceutical Company Limited announced an
exclusive licensing agreement for the commercialization and further
clinical development of cabozantinib for all future indications in
Japan, including RCC.
Cabozantinib is not indicated for the treatment of refractory
mUC and other genitourinary tumors.
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 promotion of new
medicines with the potential to improve care and outcomes for
people with cancer. Since its founding in 1994, three products
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 further
evaluation of cabozantinib in combination with immunotherapies to
treat a variety of genitourinary tumors; future data results from
expansion cohorts assessing cabozantinib and nivolumab in bladder,
renal and rare genitourinary cancer patients; 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 “may,”
“further,” “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: 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; the availability of data
at the referenced times; 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 relationships with Ipsen and
Takeda, including, the level of their 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 November 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.
1.
The University of Arizona Cancer Center.
What are genitourinary cancers?
http://uacc.arizona.edu/patients/clinic/gucancer/what-are-gu-cancers.
Accessed September 27, 2016.
2. American Cancer Society. Cancer Facts & Figures 2016.
Atlanta: American Cancer Society; 2016. 3. Jonasch E., Gao J.,
Rathmell W.K., Renal cell carcinoma. BMJ. 2014; 349:g4797. 4.
Decision Resources Report: Renal Cell Carcinoma. October 2014
(internal data on file). 5.
American Cancer Society. Key statistics
for prostate cancer. Available at
http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics.
Accessed September 28, 2016.
6.
American Cancer Society. Survival rates
for prostate cancer. Available at
http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-survival-rates.
Accessed September 28, 2016.
7.
National Cancer Institute. SEER Stat Fact
Sheets: Prostate Cancer. Available at
http://seer.cancer.gov/statfacts/html/prost.html. Accessed
September 28, 2016.
8.
Hurwitz, M. et al. Urothelial and Kidney
Cancers. Cancer Management.
http://www.cancernetwork.com/cancer-management/urothelial-and-kidney-cancers.
Accessed September 27, 2016.
9.
American Cancer Society. Bladder Cancer
Key Statistics.
http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics.
Accessed May 23, 2016.
10.
National Cancer Institute. SEER Stat Fact
Sheets: Bladder Cancer.
http://seer.cancer.gov/statfacts/html/urinb.html. Accessed May 23,
2016.
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Investors:Exelixis, Inc.Susan Hubbard, 650-837-8194EVP,
Public Affairs andInvestor
Relationsshubbard@exelixis.comorMedia:Exelixis, Inc.Lindsay
Treadway, 650-837-7522Director, Public Affairs andAdvocacy
Relationsltreadway@exelixis.com
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