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– Approval based on statistically significant and clinically meaningful overall survival benefit demonstrated in the CELESTIAL phase 3 pivotal trial –
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CABOMETYX® Tablets 60 mg, 40 mg, 20 mg (Photo: Business Wire)
“This new indication for CABOMETYX is an important treatment advance for
patients with this aggressive form of liver cancer, a community in need
of new therapeutic options,” said
The FDA’s approval of CABOMETYX was based on results from the CELESTIAL
phase 3 pivotal trial of CABOMETYX for patients with advanced HCC who
received prior sorafenib. CABOMETYX demonstrated a statistically
significant and clinically meaningful improvement in overall survival
(OS) versus placebo. On
“Patients with this form of advanced liver cancer have few treatment
options, particularly once their disease progresses following treatment
with sorafenib,” said Ghassan K. Abou-Alfa, M.D.,
In the pivotal CELESTIAL trial, median OS was 10.2 months with cabozantinib versus 8.0 months with placebo (HR 0.76, 95 percent CI 0.63-0.92; p=0.0049). Median progression-free survival (PFS) was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo (HR 0.44, 95 percent CI 0.36-0.52; p<0.0001). Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo (p=0.0086). Disease control (partial response or stable disease) was achieved by 64 percent of patients in the cabozantinib group compared with 33 percent of patients in the placebo group.
Adverse events in CELESTIAL were consistent with the known safety profile of cabozantinib. The most common (≥10 percent) grade 3 or 4 adverse events in the cabozantinib group compared to the placebo group were palmar-plantar erythrodysesthesia (17 percent vs. 0 percent), hypertension (16 percent vs. 2 percent), increased aspartate aminotransferase (12 percent vs. 7 percent), fatigue (10 percent vs. 4 percent) and diarrhea (10 percent vs. 2 percent). Treatment-related grade 5 adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome) and in one patient in the placebo group (hepatic failure). Sixteen percent of patients in the cabozantinib arm and three percent of patients in the placebo arm discontinued treatment due to treatment-related adverse events.
“While we’ve seen some progress in the treatment of primary liver cancer
in recent years, the patient community still needs new and better
About the CELESTIAL Study
CELESTIAL is a randomized, double-blind, placebo-controlled study of
cabozantinib in patients with advanced HCC conducted at more than 100
sites globally in 19 countries. The trial was designed to enroll 760
patients with advanced HCC who received prior sorafenib and may have
received up to two prior systemic cancer therapies for HCC and had
adequate liver function. Enrollment of the trial was completed in
Liver cancer is a leading cause of cancer death worldwide, accounting for more than 700,000 deaths and 800,000 new cases each year.3 In the U.S., the incidence of liver cancer has more than tripled since 1980.4 HCC is the most common form of liver cancer, making up about three-fourths of the estimated nearly 42,000 new cases in the U.S. in 2019.4 HCC is the fastest-rising cause of cancer-related death in the U.S.1 Without treatment, patients with advanced HCC usually survive less than 6 months.5
About CABOMETYX® (cabozantinib)
CABOMETYX tablets are approved in
U.S. Important Safety Information
- Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
- Perforations and Fistulas: GastrointestinaI (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed 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 event requiring medical intervention.
- Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% 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. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
- Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
- Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% 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.
- Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. 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 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.
- Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding 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.
- 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 commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.
- 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.
- 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. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
Founded in 1994,
Exelixis Forward-Looking Statements
This press release contains forward-looking statements, including,
without limitation, statements related to: Exelixis’ preparedness to
fully support the indication of previously treated advanced HCC
immediately; Exelixis’ plans to continue to explore how CABOMETYX may
benefit people with difficult-to-treat cancers beyond RCC; the potential
for CABOMETYX to become an important new therapy that slows disease
progression and improves treatment outcomes for patients with HCC who
have progressed following treatment with sorafenib; and Exelixis’ plans
to reinvest in its business to maximize the potential of the company’s
pipeline, including through targeted business development activities and
internal drug discovery. 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 degree of
market acceptance of CABOMETYX and the availability of sufficient
coverage and adequate reimbursement for this product; the strength of
CABOMETYX sales efforts, marketing, medical affairs and distribution
support; the effectiveness of CABOMETYX in comparison to competing
products; uncertainties inherent in the product development process; the
level of costs associated with Exelixis’ cabozantinib development
activities; Exelixis’ continuing compliance with applicable legal and
regulatory requirements; Exelixis’ ability to protect its intellectual
property rights; Exelixis’ dependence on third-party vendors for the
manufacture and supply of cabozantinib; 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’ ability to commercialize CABOMETYX and
expand the cabozantinib development program discussed under the caption
“Risk Factors” in Exelixis’ Quarterly Report on Form 10-Q filed with the
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|1||Mittal S, El-Serag HB. Epidemiology of HCC: Consider the Population. J Clin Gastroenterol. 2013. 47:S2-S6.|
|2||Abou-Alfa, G, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018. 379:54-63.|
International Agency for Research on Cancer. GLOBOCAN 2018. Liver Fact Sheet. Available at: http://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf. Accessed January 2019.
American Cancer Society: Cancer Facts and Figures 2019. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. Accessed January 2019.
|5||Weledji E, Orock G, Ngowe M, NsaghaD. How grim is hepatocellular carcinoma? Ann Med Surg. 2014. 3:71-76.|
EVP, Public Affairs and Investor Relations
Senior Director, Public Affairs and Advocacy Relations