-- 43 percent ORR across diverse range of GU
tumors --
-- Encouraging tolerability, 40 mg
cabozantinib plus 3 mg/kg nivolumab defined as dose for subsequent
phase 2 trials --
Exelixis, Inc. (NASDAQ:EXEL) today announced results from a
phase 1 trial of cabozantinib in combination with nivolumab in
patients with previously treated genitourinary tumors. The findings
will be presented during a poster discussion session (Abstract
#774PD) on October 9 at the European Society for Medical Oncology
(ESMO) 2016 Congress, which is being held in Copenhagen, October 7
– 11, 2016.
“The treatment landscape for advanced, intractable cancers such
as metastatic urothelial carcinoma is continuously evolving and the
use of combination therapies may improve outcomes for patients in
need of new options,” said Andrea Apolo, M.D., Genitourinary
Malignancies Branch, Center for Cancer Research, National Cancer
Institute, the principal investigator of the trial. “Our previous
correlative studies have demonstrated that cabozantinib has
immunomodulatory properties that may counteract tumor-induced
immunosuppression, providing the rationale for this trial.1,2 These
promising early stage clinical findings support further
investigation of cabozantinib in combination with nivolumab in a
number of genitourinary tumors.”
Between July 2015 and September 2016, 24 patients were accrued
with metastatic urothelial carcinoma (n=7), urachal adenocarcinoma
(n=4), squamous cell carcinoma of the bladder or urethra (n=3),
germ cell tumor (n=4), castration-resistant prostate cancer (n=4),
renal cell carcinoma (n=1), or trophoblastic tumor (n=1) and were
treated in Part I of the study, which evaluated the combination of
cabozantinib and nivolumab at four dose levels. The median number
of prior systemic therapies was 3, and 10 patients had received 4
or more prior therapies. The objective response rate was 43 percent
among the 23 patients who were evaluable for response, with one
complete response and nine partial responses. Four of six patients
(67 percent) with urothelial cancer achieved a response. The
recommended doses for the ongoing expansion cohorts were determined
to be cabozantinib at 40 mg daily and nivolumab at 3 mg/kg once
every 2 weeks. Part II of the phase 1 trial examining the use of
the triplet combination of cabozantinib, nivolumab, and ipilimumab
is also ongoing.
“Cabozantinib has demonstrated clinical activity as a single
agent in several tumors, and we are interested in further examining
its potential in combination with immunotherapies to treat a
variety of genitourinary and other cancers,” said Michael M.
Morrissey, Ph.D., president and chief executive officer of
Exelixis. “We are encouraged by these preliminary phase 1 data and
look forward to results from the ongoing expansion cohorts in this
trial in patients with metastatic urothelial carcinoma and renal
cell carcinoma.”
Common grade 1/2 adverse events observed in more than 30 percent
of patients were fatigue, diarrhea, anorexia, dysgeusia,
hoarseness, and oral mucositis. Grade 3 adverse events observed in
more than 10 percent of patients, included neutropenia, fatigue,
and thromboembolic events. There was one grade 4 adverse event of
lipase elevation. No grade 5 toxicities were observed.
In addition to Part I, the study also has enrolled 15 patients
in Part II, which is evaluating the triplet combination of
cabozantinib, nivolumab, and ipilimumab. 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.3
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.4 Clear cell renal cell
carcinoma is the most common type of kidney cancer in adults.5 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.4 Approximately 30,000 patients in
the U.S. and 68,000 globally require treatment.6
Prostate cancer is the second most common cause of cancer death
in men, behind only skin cancer.7 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.8 Approximately 2,850,000 men were
living with prostate cancer in the U.S. in 2013,9 and 180,000 new
cases are diagnosed each year.7
Urothelial cancers encompass carcinomas of the bladder, ureter
and renal pelvis at a ratio of 50:3:1, respectively.10 Urothelial
carcinoma occurs mainly in older people, with 90 percent of
patients aged 55 or older.11 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.11 In 2013, an estimated
587,426 people were living with bladder cancer in the U.S.12
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.
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 commercialization of
new medicines with the potential to improve care and outcomes for
people with cancer. Since its founding in 1994, three medicines
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
therapeutic potential of cabozantinib and the further examination
of cabozantinib in combination with immunotherapies to treat a
variety of genitourinary and other cancers; future data results
from the ongoing expansion cohorts of the phase 1 trial of
cabozantinib in combination with nivolumab in patients with
metastatic urothelial carcinoma and renal cell carcinoma and from
Part II of the trial evaluating the triplet combination of
cabozantinib, nivolumab and ipilimumab; 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,”
“potential,” “look forward,” “will,” “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 relationship with Ipsen, including, the level of Ipsen’s
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 August 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.
References
1. Kwilas, A. et al. Journal of Translational Medicine 2014,
12:294 http://www.translational-medicine.com/content/12/1/294.
2. Apolo, A. et al. Effect of Cabozantinib on Immunosuppressive
Subsets in Metastatic Urothelial Carcinoma. Presented at: American
Society of Clinical Oncology 2014 Annual Meeting; May 30 – June 3,
2014; Chicago, IL.
3. 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.
4. American Cancer Society. Cancer Facts & Figures 2016.
Atlanta: American Cancer Society; 2016.
5. Jonasch E., Gao J., Rathmell W.K., Renal cell carcinoma. BMJ.
2014; 349:g4797.
6. Decision Resources Report: Renal Cell Carcinoma. October 2014
(internal data on file).
7. 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.
8. 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.
9. National Cancer Institute. SEER Stat Fact Sheets: Prostate
Cancer. Available at
http://seer.cancer.gov/statfacts/html/prost.html. Accessed
September 28, 2016.
10. Hurwitz, M. et al. Urothelial and Kidney Cancers. Cancer
Management.
http://www.cancernetwork.com/cancer-management/urothelial-and-kidney-cancers.
Accessed September 27, 2016.
11. American Cancer Society. Bladder Cancer Key Statistics.
http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics.
Accessed May 23, 2016.
12. 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,
650-837-8194Investor Relations & Public
Affairsshubbard@exelixis.comorMedia:Exelixis, Inc.Lindsay
Treadway, 650-837-7522Public Affairs & Advocacy
Relationsltreadway@exelixis.com
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