– Cabozantinib compared with placebo reduced
the risk of disease progression or death in patients with
pancreatic NET and in patients with extra-pancreatic NET –
– Exelixis will discuss the results with the
U.S. Food and Drug Administration –
Exelixis, Inc. (Nasdaq: EXEL) today announced detailed results
from CABINET, a phase 3 pivotal trial evaluating cabozantinib
(CABOMETYX®) compared with placebo in two cohorts of patients with
previously treated neuroendocrine tumors: one cohort of patients
with advanced pancreatic neuroendocrine tumors (pNET) and a second
cohort of patients with advanced extra-pancreatic NET (epNET). The
study met the primary objective for each cohort, demonstrating that
cabozantinib provided dramatic improvements in median
progression-free survival (PFS) for the patients in the pNET and
epNET cohorts. The data are being presented today at 8:40 a.m. CET
during the Proffered Paper Session – NETs and Endocrine Tumours at
the 2023 European Society of Medical Oncology (ESMO) Congress
(LBA53) by the Alliance for Clinical Trials in Oncology. CABINET is
sponsored by the National Cancer Institute (NCI), part of National
Institutes of Health, and is led by the NCI-funded Alliance for
Clinical Trials in Oncology and conducted by the NCI-funded
National Clinical Trials Network Group.
“Although progress has been made in recent years, there remains
a critical need for new and effective therapies for patients with
advanced neuroendocrine tumors. Given that there is no standard
treatment for patients with progressive disease, these results
showing notable improvements in progression-free survival are
highly encouraging for patients and their physicians,” said
Jennifer Chan, M.D., M.P.H., study chair for the CABINET trial and
Clinical Director of the Gastrointestinal Cancer Center and
Director of the Program in Carcinoid and Neuroendocrine Tumors at
Dana-Farber Cancer Institute. “I am pleased to present these
important findings at ESMO today, as they underscore the potential
of cabozantinib as a much-needed new treatment option for this
disease, which is rising in incidence.”
As announced in August, CABINET was stopped and unblinded early
due to the dramatic improvement in efficacy observed at an interim
analysis, per a unanimous recommendation of the Alliance for
Clinical Trials in Oncology independent Data and Safety Monitoring
Board (DSMB). The DSMB based their vote on data from interim
analyses of PFS using local radiology assessments. Ancillary
analyses were conducted using local and central assessments of
patients enrolled through June 2023.
Results from the CABINET study presented today at ESMO
demonstrate that treatment with cabozantinib resulted in compelling
improvements in PFS based both on local review and on independent
blinded central radiology review. In the pNET cohort, at a median
follow-up of 16.7 months, median PFS based on local radiology
review was 11.4 months for patients receiving cabozantinib compared
with 3.0 months for patients receiving placebo (stratified hazard
ratio [HR]: 0.27; 95% confidence interval [CI]: 0.14-0.49;
p<0.0001). The HR for PFS based on blinded independent central
radiology review was 0.25 (95% CI: 0.12-0.54; p<0.0001). In the
epNET cohort, at a median follow-up of 13.9 months, median PFS
based on local radiology review was 8.3 months in patients
receiving cabozantinib compared with 3.2 months for patients
receiving placebo (stratified HR: 0.45; 95% CI: 0.30-0.66;
p<0.0001). The HR for PFS based on blinded independent central
radiology review was 0.50 (95% CI: 0.32-0.79; p<0.0001).
The safety profile of cabozantinib observed in each cohort was
consistent with its known safety profile; no new safety signals
were identified.
For patients with advanced NET, treatment options include
somatostatin analogs, targeted therapy, Lu-177 dotatate, which is a
form of peptide-receptor radionuclide therapy, or chemotherapy.
Over half of patients in each cohort received prior everolimus or
prior Lu-177 dotatate.
“We are pleased to share these details of cabozantinib in
patients with advanced neuroendocrine tumors who have limited
treatment options,” said Amy Peterson, M.D., Executive Vice
President, Product Development & Medical Affairs, and Chief
Medical Officer, Exelixis. “We look forward to discussing these
findings with the U.S. Food and Drug Administration so that we may
potentially bring an active therapy to patients with these
aggressive, difficult-to-treat cancers.”
About CABINET (A021602)
CABINET (Randomized, Double-Blinded Phase III Study of
CABozantinib versus Placebo In Patients with Advanced
NEuroendocrine Tumors After Progression on Prior
Therapy) is sponsored by the NCI, part of the National Institutes
of Health, and is being led and conducted by the NCI-funded
Alliance for Clinical Trials in Oncology with participation from
the NCI-funded National Clinical Trials Network as part of
Exelixis’ collaboration through a Cooperative Research and
Development Agreement with the NCI’s Cancer Therapy Evaluation
Program.
CABINET is a multicenter, randomized, double-blinded,
placebo-controlled phase 3 pivotal trial that enrolled a total of
290 patients in the U.S. Patients were randomized 2:1 to
cabozantinib or placebo in two separate cohorts (pNET, n=93; epNET,
n=197). The epNET cohort included patients with the following
primary tumor sites: gastrointestinal (GI) tract, lung, unknown and
other. Each cohort was randomized separately and had its own
statistical analysis plan. Patients must have had measurable
disease per RECIST 1.1 criteria and must have experienced disease
progression after at least one U.S. Food and Drug
Administration-approved line of prior therapy other than
somatostatin analogs. The primary endpoint in each cohort was PFS
per RECIST 1.1 by retrospective independent central review. Upon
confirmation of disease progression, patients were unblinded, and
those receiving placebo were permitted to cross over to open-label
therapy with cabozantinib. Secondary endpoints included overall
survival, radiographic response rate and safety. More information
about this trial is available at ClinicalTrials.gov.
About Neuroendocrine Tumors (NET)
NET are cancers that begin in the specialized cells of the
body’s neuroendocrine system.1 These cells have traits of both
hormone-producing endocrine cells and nerve cells.1 In the U.S.,
more than 12,000 people are diagnosed with NET each year and
approximately 171,000 people are living with the disease.2 The
number of people diagnosed with NET each year has been increasing.2
NET are classified as functional or non-functional.1 Functional NET
release peptide hormones that can cause debilitating symptoms and
necessitate treatment, while symptoms of non-functional NET are
related primarily to tumor growth.1,3,4 Most NET take years to
develop and grow slowly, but some grow quickly, especially after
progression on standard therapy.5
NET can develop in any part of the body, but most commonly start
in the GI tract or in the lungs, where they have historically been
referred to as carcinoid tumors and are more recently called
epNET.5 The five-year survival rates for advanced GI-NET and lung
carcinoid tumors are 68% and 55%, respectively.6,7 Less commonly,
NET can also start in the pancreas, where they tend to be more
aggressive, with a five-year survival rate of only 23% for advanced
disease.8,9 Surgery to remove the tumor and prevent it from
spreading is the typical first approach to treatment.10 For more
advanced disease, options include somatostatin analogs, targeted
therapy and peptide-receptor radionuclide therapy.10
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced renal cell carcinoma (RCC); for the
treatment of patients with hepatocellular carcinoma (HCC) who have
been previously treated with sorafenib; for patients with advanced
RCC as a first-line treatment in combination with nivolumab; and
for adult and pediatric patients 12 years of age and older with
locally advanced or metastatic differentiated thyroid cancer (DTC)
that has progressed following prior VEGFR-targeted therapy and who
are radioactive iodine-refractory or ineligible. CABOMETYX tablets
have also received regulatory approvals in the European Union and
additional countries and regions worldwide. In 2016, Exelixis
granted Ipsen Pharma SAS exclusive rights for the commercialization
and further clinical development of cabozantinib outside of the
U.S. and Japan. In 2017, Exelixis granted exclusive rights to
Takeda for the commercialization and further clinical development
of cabozantinib for all future indications in Japan. Exelixis holds
the exclusive rights to develop and commercialize cabozantinib in
the U.S.
CABOMETYX is not indicated as a treatment for NET.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with
CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5%
in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue
CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as
recommended. Do not administer CABOMETYX to patients who have a
recent history of hemorrhage, including hemoptysis, hematemesis, or
melena.
Perforations and Fistulas: Fistulas, including fatal
cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI)
perforations, including fatal cases, occurred in 1% of CABOMETYX
patients. Monitor patients for signs and symptoms of fistulas and
perforations, including abscess and sepsis. Discontinue CABOMETYX
in patients who experience a Grade 4 fistula or a GI
perforation.
Thrombotic Events: CABOMETYX increased the risk of
thrombotic events. Venous thromboembolism occurred in 7% (including
4% pulmonary embolism) and arterial thromboembolism in 2% of
CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX
patients. Discontinue CABOMETYX in patients who develop an acute
myocardial infarction or serious arterial or venous thromboembolic
events that require medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause
hypertension, including hypertensive crisis. Hypertension was
reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX
patients. Do not initiate CABOMETYX in patients with uncontrolled
hypertension. Monitor blood pressure regularly during CABOMETYX
treatment. Withhold CABOMETYX for hypertension that is not
adequately controlled with medical management; when controlled,
resume at a reduced dose. Permanently discontinue CABOMETYX for
severe hypertension that cannot be controlled with
anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients.
Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and
manage patients using antidiarrheals as indicated. Withhold
CABOMETYX until improvement to ≤ Grade 1, resume at a reduced
dose.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in
45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX
patients. Withhold CABOMETYX until improvement to Grade 1 and
resume at a reduced dose for intolerable Grade 2 PPE or Grade 3
PPE.
Hepatotoxicity: CABOMETYX in combination with nivolumab
can cause hepatic toxicity with higher frequencies of Grades 3 and
4 ALT and AST elevations compared to CABOMETYX alone.
Monitor liver enzymes before initiation of and periodically
throughout treatment. Consider more frequent monitoring of liver
enzymes than when the drugs are administered as single agents. For
elevated liver enzymes, interrupt CABOMETYX and nivolumab and
consider administering corticosteroids.
With the combination of CABOMETYX and nivolumab, Grades 3 and 4
increased ALT or AST were seen in 11% of patients. ALT or AST >3
times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%)
received systemic corticosteroids; ALT or AST resolved to Grades
0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT
or AST who were rechallenged with either CABOMETYX (n=9) or
nivolumab (n=11) as a single agent or with both (n=24), recurrence
of Grade ≥2 increased ALT or AST was observed in 2 patients
receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients
receiving both CABOMETYX and nivolumab. Withhold and resume at a
reduced dose based on severity.
Adrenal Insufficiency: CABOMETYX in combination with
nivolumab can cause primary or secondary adrenal insufficiency. For
Grade 2 or higher adrenal insufficiency, initiate symptomatic
treatment, including hormone replacement as clinically indicated.
Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a
reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with
RCC who received CABOMETYX with nivolumab, including Grade 3
(2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency
led to permanent discontinuation of CABOMETYX and nivolumab in 0.9%
and withholding of CABOMETYX and nivolumab in 2.8% of patients with
RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency
received hormone replacement therapy, including systemic
corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the
15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was
withheld for adrenal insufficiency, 6 reinstated treatment after
symptom improvement; of these, all (n=6) received hormone
replacement therapy and 2 had recurrence of adrenal
insufficiency.
Proteinuria: Proteinuria was observed in 8% of CABOMETYX
patients. Monitor urine protein regularly during CABOMETYX
treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until
improvement to ≤ Grade 1 proteinuria; resume CABOMETYX at a
reduced dose. Discontinue CABOMETYX in patients who develop
nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of
CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis,
osteitis, bone erosion, tooth or periodontal infection, toothache,
gingival ulceration or erosion, persistent jaw pain, or slow
healing of the mouth or jaw after dental surgery. Perform an oral
examination prior to CABOMETYX initiation and periodically during
treatment. Advise patients regarding good oral hygiene practices.
Withhold CABOMETYX for at least 3 weeks prior to scheduled dental
surgery or invasive dental procedures, if possible. Withhold
CABOMETYX for development of ONJ until complete resolution, resume
at a reduced dose.
Impaired Wound Healing: Wound complications occurred with
CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to
elective surgery. Do not administer CABOMETYX for at least 2 weeks
after major surgery and until adequate wound healing. The safety of
resumption of CABOMETYX after resolution of wound healing
complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
RPLS, a syndrome of subcortical vasogenic edema diagnosed by
characteristic findings on MRI, can occur with CABOMETYX. Evaluate
for RPLS in patients presenting with seizures, headache, visual
disturbances, confusion, or altered mental function. Discontinue
CABOMETYX in patients who develop RPLS.
Thyroid Dysfunction: Thyroid dysfunction, primarily
hypothyroidism, has been observed with CABOMETYX. Based on the
safety population, thyroid dysfunction occurred in 19% of patients
treated with CABOMETYX, including Grade 3 in 0.4% of patients.
Patients should be assessed for signs of thyroid dysfunction
prior to the initiation of CABOMETYX and monitored for signs and
symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid
function testing and management of dysfunction should be performed
as clinically indicated.
Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on
the safety population, hypocalcemia occurred in 13% of patients
treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1%
of patients. Laboratory abnormality data were not collected in
CABOSUN.
In COSMIC-311, hypocalcemia occurred in 36% of patients treated
with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of
patients.
Monitor blood calcium levels and replace calcium as necessary
during treatment. Withhold and resume at reduced dose upon recovery
or permanently discontinue CABOMETYX depending on severity.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm.
Advise pregnant women and females of reproductive potential of the
potential risk to a fetus. Verify the pregnancy status of females
of reproductive potential prior to initiating CABOMETYX and advise
them to use effective contraception during treatment and for 4
months after the last dose.
ADVERSE REACTIONS
The most common (≥20%) adverse reactions are:
CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased
appetite, hypertension, nausea, vomiting, weight decreased, and
constipation.
CABOMETYX in combination with nivolumab: diarrhea, fatigue,
hepatotoxicity, PPE, stomatitis, rash, hypertension,
hypothyroidism, musculoskeletal pain, decreased appetite, nausea,
dysgeusia, abdominal pain, cough, and upper respiratory tract
infection.
DRUG INTERACTIONS
Strong CYP3A4 Inhibitors: If coadministration with strong
CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage.
Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong
CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Avoid St. John’s wort.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during
CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic
impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in
patients with severe hepatic impairment.
Please see accompanying full Prescribing Information
https://www.cabometyx.com/downloads/CABOMETYXUSPI.pdf.
You are encouraged to report negative side effects of
prescription drugs to the FDA. Visit www.FDA.gov/medwatch or
call 1-800-FDA-1088.
About Exelixis
Exelixis is a globally ambitious oncology company innovating
next-generation medicines and regimens at the forefront of cancer
care. Powered by bi-coastal centers of discovery and development
excellence, we are rapidly evolving our product portfolio to target
an expanding range of tumor types and indications with our
clinically differentiated pipeline of small molecules,
antibody-drug conjugates and other biotherapeutics. This
comprehensive approach harnesses decades of robust investment in
our science and partnerships to advance our investigational
programs and extend the impact of our flagship commercial product,
CABOMETYX® (cabozantinib). Exelixis is driven by a bold scientific
pursuit to create transformational treatments that give more
patients hope for the future. For information about the company and
its mission to help cancer patients recover stronger and live
longer, visit www.exelixis.com, follow @ExelixisInc on X (Twitter),
like Exelixis, Inc. on Facebook and follow Exelixis on
LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: Exelixis’
presentation of data from CABINET during the Proffered Paper
Session at the 2023 ESMO Congress; the therapeutic potential of
cabozantinib to reduce the risk of disease progression or death for
patients with previously treated advanced pNET or advanced epNET;
Exelixis’ plans to discuss the trial data from CABINET with the
FDA; and Exelixis’ scientific pursuit to create transformational
treatments that give more patients hope for the future. 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 availability of data at the referenced
times; complexities and the unpredictability of the regulatory
review and approval processes in the U.S. and elsewhere; Exelixis’
continuing compliance with applicable legal and regulatory
requirements; Exelixis’ dependence on its relationships with its
cabozantinib commercial collaboration partners, including the level
of their investment in the resources necessary to pursue regulatory
approvals and successfully commercialize cabozantinib in the
territories where approved; 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 CABOMETYX;
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, 2023 and Annual Report on Form 10-K filed with the SEC on
February 7, 2023, 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, except as required
by law.
Exelixis, the Exelixis logo and CABOMETYX are
registered U.S. trademarks of Exelixis.
1 Neuroendocrine Tumors: Introduction. Cancer.Net website.
Available at:
https://www.cancer.net/cancer-types/neuroendocrine-tumors/introduction.
Accessed October 2023.
2 Neuroendocrine Tumors: Statistics. Cancer.Net website.
Available at:
https://www.cancer.net/cancer-types/neuroendocrine-tumors/statistics.
Accessed October 2023.
3 Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment
(PDQ®)–Patient Version. NCI website. Available at:
https://www.cancer.gov/types/pancreatic/patient/pnet-treatment-pdq.
Accessed October 2023.
4 Neuroendocrine Tumors: Types of Treatment. Cancer.Net website.
Available at:
https://www.cancer.net/cancer-types/neuroendocrine-tumors/types-treatment.
Accessed October 2023.
5 Neuroendocrine Tumor of the Gastrointestinal Tract:
Introduction. Cancer.Net website. Available at:
https://www.cancer.net/cancer-types/neuroendocrine-tumor-gastrointestinal-tract/introduction.
Accessed October 2023.
6 Survival Rates for Gastrointestinal Carcinoid Tumors. ACS
website. Available at:
https://www.cancer.org/cancer/types/gastrointestinal-carcinoid-tumor/detection-diagnosis-staging/survival-rates.html.
Accessed October 2023.
7 Survival Rates for Lung Carcinoid Tumors. ACS website.
Available at:
https://www.cancer.org/cancer/types/lung-carcinoid-tumor/detection-diagnosis-staging/survival-rates.html.
Accessed October 2023.
8 Neuroendocrine Tumor of the Pancreas: Statistics. Cancer.Net
website. Available at:
https://www.cancer.net/cancer-types/neuroendocrine-tumor-pancreas/statistics.
Accessed October 2023.
9 Survival Rates for Pancreatic Neuroendocrine Tumor. ACS
website. Available at:
https://www.cancer.org/cancer/types/pancreatic-neuroendocrine-tumor/detection-diagnosis-staging/survival-rates.html.
Accessed October 2023.
10 Neuroendocrine Tumor (NET). NCI website. Availably at:
https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-endocrine-tumor/carcinoid-tumor.
Accessed October 2023.
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version on businesswire.com: https://www.businesswire.com/news/home/20231020586023/en/
Investors: Susan Hubbard EVP, Public Affairs and Investor
Relations Exelixis, Inc. (650) 837-8194 shubbard@exelixis.com
Media: Claire McConnaughey Senior Director, Public
Affairs Exelixis, Inc. (650) 837-7052 cmcconn@exelixis.com
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