– The FDA assigned a Prescription Drug User
Fee Act target action date of April 3, 2025 –
– Application is based on results from the
phase 3 CABINET pivotal trial, in which cabozantinib provided a
statistically significant and clinically meaningful improvement in
progression-free survival versus placebo –
Exelixis, Inc. (Nasdaq: EXEL) today announced that its
supplemental New Drug Application (sNDA) for cabozantinib
(CABOMETYX®) has been accepted in the U.S. for: 1) the treatment of
adults with previously treated, locally advanced/unresectable or
metastatic, well- or moderately differentiated pancreatic
neuroendocrine tumors (pNET), and 2) the treatment of adults with
previously treated, locally advanced/unresectable or metastatic,
well- or moderately differentiated extra-pancreatic NET (epNET).
The U.S. Food and Drug Administration (FDA) also granted orphan
drug designation to cabozantinib for the treatment of pNET. The FDA
assigned a standard review with a Prescription Drug User Fee Act
target action date of April 3, 2025.
“The FDA’s acceptance of this application marks another
important milestone in our commitment to bringing cabozantinib to
patients living with difficult-to-treat cancers and who have
limited treatment options,” said Amy Peterson, M.D., Executive Vice
President, Product Development & Medical Affairs, and Chief
Medical Officer, Exelixis. “We appreciate the opportunity to work
with the FDA in the coming months as they review our application,
with the goal to bring this new, effective treatment option to
patients with advanced neuroendocrine tumors as quickly as
possible.”
The sNDA is based on the final results of the phase 3 CABINET
pivotal trial evaluating cabozantinib compared with placebo in two
cohorts of patients with previously treated NET: advanced pNET and
advanced epNET. As previously announced, CABINET was stopped early
for compelling activity; all patients were unblinded and those on
placebo were given the option to cross over to active treatment
with cabozantinib. This early stopping was due to a dramatic
improvement in progression-free survival (PFS) observed at an
interim analysis in both cohorts. The study demonstrated a
statistically significant and clinically meaningful improvement in
PFS with cabozantinib versus placebo, based on results of both
local review and available independent blinded central radiology
review. Initial results were presented at the 2023 European Society
of Medical Oncology (ESMO) Congress; final results will be
presented at the 2024 ESMO Congress on September 16th in Barcelona,
Spain.
About CABINET (Alliance 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 National Cancer Institute (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 had enrolled a total
of 290 patients in the U.S. at the time of the interim analysis.
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 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 or intolerance after
at least one U.S. FDA-approved line of prior therapy other than
somatostatin analogs. The primary endpoint in each cohort was PFS
per RECIST 1.1 by retrospective blinded independent central review.
Upon 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) Neuroendocrine tumors
(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., it
is estimated that 161,000 to 192,000 people are living with
unresectable, locally advanced or metastatic NET.2 The number of
people diagnosed with NET has been increasing in recent decades.3
Functional NET release peptide hormones that can cause debilitating
symptoms, like diarrhea, hypertension and flushing, which may
require focused treatment, while symptoms of non-functional NET are
related primarily to tumor growth.4,5 Most NET take years to
develop and grow slowly, but eventually, all patients with advanced
or metastatic NET will develop refractory and progressing
disease.6,7
NET can develop in any part of the body but most commonly start
in the gastrointestinal (GI) tract or in the lungs, where they have
historically been referred to as carcinoid tumors and are more
recently called epNET.1 The five-year survival rates for advanced
GI and lung NET are 68% and 55%, respectively.8,9 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.1,10 For
advanced NET patients, treatment options include somatostatin
analogs, chemotherapy, targeted therapy and peptide-receptor
radionuclide therapy.11
About CABOMETYX® (cabozantinib) In the U.S.,
CABOMETYX tablets are approved as monotherapy for the treatment of
patients with advanced renal cell carcinoma (RCC) and in
combination with nivolumab as a first-line treatment for patients
with advanced RCC; for the treatment of patients with
hepatocellular carcinoma (HCC) who have been previously treated
with sorafenib; 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 Pharmaceutical Company
Limited 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 drug 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: the therapeutic potential of cabozantinib as
a treatment for patients with previously treated, locally
advanced/unresectable or metastatic, well- or moderately
differentiated pNET and epNET; the regulatory review process,
including the PDUFA target action date assigned by the FDA, and
Exelixis’ plans to work with the FDA while the application is
reviewed; and Exelixis’ scientific pursuit to create
transformational treatments that give patients more 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: complexities and the unpredictability of the
regulatory review and approval processes in the U.S. and elsewhere,
including the risk that the FDA may not approve cabozantinib as a
treatment for pNET or epNET in a timely fashion, if at all;
unexpected concerns that may arise as a result of the occurrence of
adverse safety events or additional data analyses of clinical
trials evaluating 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 the ability of Exelixis to obtain
regulatory approval for cabozantinib in new indications detailed
from time to time under the caption “Risk Factors” in Exelixis’
most recent Annual Report on Form 10-K and subsequent Quarterly
Reports on Form 10-Q, and in Exelixis’ future filings with the
Securities and Exchange Commission. 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. Cleveland Clinic website. Available at:
https://my.clevelandclinic.org/health/diseases/22006-neuroendocrine-tumors-net.
Accessed August 2024. 2 Population Estimate: Unresectable, Locally
Advanced or Metastatic Extra-Pancreatic NET. June 2024 (internal
data on file). 3 Pathak S, Starr JS, Halfdanarson T, et al.
Understanding the increasing incidence of neuroendocrine tumors.
Expert Rev Endocrinol Metab. September 2023;18(5):377-385. 4
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 August 2024. 5 What Is a Pancreatic Neuroendocrine Tumor?
ACS website. Available at:
https://www.cancer.org/cancer/types/pancreatic-neuroendocrine-tumor/about/what-is-pnet.html.
Accessed August 2024. 6 McClellan K, Chen EY, Kardosh A, et al.
Therapy Resistant Gastroenteropancreatic Neuroendocrine Tumors.
Cancers. 2022, 14(19), 4769. 7 What is a Gastrointestinal Carcinoid
Tumor? ACS website. Available at:
https://www.cancer.org/cancer/types/gastrointestinal-carcinoid-tumor/about/what-is-gastrointestinal-carcinoid.html.
Accessed August 2024. 8 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 August 2024. 9 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 August 2024. 10 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 August 2024. 11 Neuroendocrine Tumor (NET). NCI website.
Available at:
https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-endocrine-tumor/carcinoid-tumor.
Accessed August 2024.
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version on businesswire.com: https://www.businesswire.com/news/home/20240805262570/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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