Exelixis, Inc. (Nasdaq: EXEL) today announced that the U.S. Food
and Drug Administration (FDA) has notified the company that the
supplemental New Drug Application (sNDA) for cabozantinib
(CABOMETYX®) for the treatment of adults with previously treated
advanced pancreatic neuroendocrine tumors (pNET) and advanced
extra-pancreatic NET (epNET) will be discussed at an Oncologic
Drugs Advisory Committee (ODAC) meeting in March 2025. The sNDA is
based on the final results of the phase 3 CABINET pivotal trial,
conducted by the National Cancer Institute's National Clinical
Trials Network, evaluating cabozantinib compared with placebo in
advanced pNET and advanced epNET. In August 2024, Exelixis
announced that the FDA granted orphan drug designation to
cabozantinib for the treatment of pNET and assigned a Prescription
Drug User Fee Act target action date of April 3, 2025.
As announced in August 2023, the Alliance for Clinical Trials in
Oncology independent Data and Safety Monitoring Board unanimously
recommended that enrollment in the CABINET trial be stopped and
randomized patients be unblinded to therapy with the allowance for
crossover from placebo to cabozantinib due to the substantial
improvement in progression-free survival (PFS) observed at this
interim analysis. Final results from the enrolled patient
population, which were presented at the 2024 European Society of
Medical Oncology Congress and published concurrently in the New
England Journal of Medicine, confirmed statistically significant
and clinically meaningful improvements with cabozantinib versus
placebo in the primary endpoint of PFS by blinded independent
central review. Additional analyses supported consistency of
benefit across all clinical subgroups examined, including primary
tumor site, grade and prior systemic anticancer therapy.
ODACs review and evaluate data regarding the safety and
effectiveness of marketed and investigational human drug products
for use in the treatment of cancer and make recommendations to the
Commissioner of Food and Drugs. More general information about ODAC
reviews can be found on the FDA website, here. The planned ODAC
meeting is not related to the current approved indications for
CABOMETYX in the U.S.
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 298 patients in the U.S at the time of the final analysis.
Patients were randomized 2:1 to cabozantinib (60 mg) or placebo in
two separately powered cohorts (pNET, n=95; epNET, n=203). The
epNET cohort included patients with the following primary tumor
sites: gastrointestinal (GI) tract, lung, unknown primary sites 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 blinded
independent central review. 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., 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 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
tumors 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 for patients 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 over 65 countries outside the U.S.
and Japan, including the European Union. 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. 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
http://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.
Exelixis Forward-Looking Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: the FDA’s
plans to discuss the sNDA for cabozantinib for the treatment of
adults with previously treated advanced pNET and advanced epNET at
an ODAC meeting in March 2025; the therapeutic potential of
cabozantinib as a treatment for patients with previously treated
advanced pNET and advanced epNET; the regulatory review process
with respect to Exelixis’ sNDA for cabozantinib in previously
treated advanced pNET and advanced epNET, including the
Prescription Drug User Fee Act target action date assigned by the
FDA; 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 November 2024. 2 Population Estimate: Unresectable,
Locally Advanced or Metastatic Extra-Pancreatic NET. June 2024
(internal data on file). 3 Pathak, S., Starr, J.S., 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 November 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 November 2024. 6 McClellan, K., Chen. E.Y, 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 November 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 November 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 November 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 November 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 November 2024.
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version on businesswire.com: https://www.businesswire.com/news/home/20241126525837/en/
Investors Contact: Susan Hubbard EVP, Public Affairs and
Investor Relations Exelixis, Inc. (650) 837-8194
shubbard@exelixis.com
Media Contact: Lindsay Treadway VP, Public Affairs and
Advocacy Relations Exelixis, Inc. (650) 837-7522
ltreadway@exelixis.com
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