– CABOMETYX recommended for the treatment of
previously untreated advanced renal cell carcinoma across all
patient risk groups –
Exelixis, Inc. (NASDAQ:EXEL) today announced that the National
Comprehensive Cancer Network (NCCN) updated its Clinical Practice
Guidelines to include new recommendations for CABOMETYX®
(cabozantinib) tablets. With the updates, CABOMETYX is recommended
by the NCCN for the treatment of advanced renal cell carcinoma
(RCC) regardless of patient risk status (favorable-, intermediate-,
and poor-risk).
Key CABOMETYX-related highlights from the updated NCCN Clinical
Practice Guidelines for Kidney Cancer include:1
- CABOMETYX is the only preferred
tyrosine kinase inhibitor (TKI) treatment option for first-line
patients in the poor- and intermediate-risk groups (Category
2A)
- CABOMETYX is a recommended first-line
treatment option for favorable-risk patients (Category 2B)
- CABOMETYX is the only preferred TKI
treatment option for previously treated patients (Category 1)
“CABOMETYX is the only TKI indicated for the treatment of
advanced kidney cancer with NCCN-preferred status for intermediate-
and poor-risk groups in the first-line setting and the only TKI
with preferred status for patients who have progressed on prior
therapy,” said Michael M. Morrissey, Ph.D., President and Chief
Executive Officer of Exelixis. “We welcome these updated
recommendations, which recognize the significance of the CABOSUN
trial data included in our label as an important advance in the
care of patients with this disease.”
The NCCN Clinical Practice Guidelines are the recognized
standard for clinical policy in cancer care and are developed
through review of evidence and recommendations from physicians and
oncology researchers. The NCCN kidney cancer panel’s decision to
include CABOMETYX as a Category 2A preferred option for the
treatment of patients with previously untreated advanced RCC with
poor- or intermediate-risk disease was based on the results of the
phase 2 CABOSUN trial.
Additionally, in its recent update to the Clinical Practice
Guidelines for Hepatobiliary Cancers, the NCCN added cabozantinib
as a Category 1 option for the treatment of patients with
hepatocellular carcinoma (HCC) (Child-Pugh Class A only) who have
been previously treated with sorafenib.2 CABOMETYX is not
FDA-approved for previously treated advanced HCC. On May 29, 2018,
the U.S. FDA accepted the supplemental New Drug Application for
CABOMETYX in previously treated advanced HCC and assigned it a
Prescription Drug User Fee Act (PDUFA) action date of January 14,
2019.
Please see Important Safety Information below and full U.S.
prescribing information at
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About the CABOSUN Study
On May 23, 2016, Exelixis announced that the
phase 2 CABOSUN study met its primary endpoint, demonstrating a
statistically significant and clinically meaningful improvement in
PFS compared with sunitinib in patients with advanced intermediate-
or poor-risk RCC as determined by investigator assessment. The
CABOSUN study was conducted by The Alliance for Clinical
Trials in Oncology and was sponsored by the National Cancer
Institute-Cancer Therapy Evaluation Program (NCI-CTEP) under
the Cooperative Research and Development Agreement
with Exelixis for the development of cabozantinib. These
results were first presented by Dr. Toni Choueiri at
the European Society for Medical Oncology (ESMO)
2016 Congress, and published in the Journal of Clinical
Oncology (Choueiri, JCO, 2016).3 In June 2017, a
blinded independent radiology review committee (IRC) confirmed that
cabozantinib provided a clinically meaningful and statistically
significant improvement in the primary efficacy endpoint of
investigator-assessed PFS. Results from the IRC review were
presented by Dr. Toni Choueiri at the ESMO
2017 Congress.
CABOSUN was a randomized, open-label, active-controlled phase 2
trial that enrolled 157 patients with advanced RCC determined to be
intermediate- or poor-risk by the IMDC criteria. Patients were
randomized 1:1 to receive cabozantinib (60 mg once daily) or
sunitinib (50 mg once daily, 4 weeks on followed by 2 weeks off).
The primary endpoint was PFS. Secondary endpoints included overall
survival, objective response rate and safety. Eligible patients
were required to have locally advanced or metastatic clear-cell
RCC, ECOG performance status 0-2 and had to be intermediate- or
poor-risk per the IMDC criteria (Heng, JCO, 2009).4 Prior
systemic treatment for RCC was not permitted.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2018 statistics cite kidney cancer
as among the top ten most commonly diagnosed forms of cancer among
both men and women in the U.S.5 Clear cell RCC is the most
common type of kidney cancer in adults.6 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.7 Approximately 30,000 patients in the U.S.
and 68,000 globally require treatment, and an estimated 14,000
patients in the U.S. each year are in need of a first-line
treatment for advanced kidney cancer.7
The majority of clear cell RCC tumors have lower than normal
levels of a protein called von Hippel-Lindau, which leads to higher
levels of MET, AXL and VEGF.8,9 These proteins promote tumor
angiogenesis (blood vessel growth), growth, invasiveness and
metastasis.10,11,12,13 MET and AXL may provide escape pathways
that drive resistance to VEGF receptor inhibitors.9,10
About HCC
Liver cancer is the second-leading cause of cancer death
worldwide, accounting for more than 700,000 deaths and nearly
800,000 new cases each year.14 In the U.S., the incidence of
liver cancer has more than tripled since 1980.5 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
2018.5 HCC is the fastest-rising cause of cancer-related death
in U.S.15 Without treatment, patients with advanced HCC
usually survive less than 6 months.16
About CABOMETYX® (cabozantinib)
CABOMETYX tablets are approved in the United States for the
treatment of patients with advanced RCC. CABOMETYX tablets are also
approved in the European Union, Norway, Iceland, Australia,
Switzerland and South Korea for the treatment of advanced RCC in
adults who have received prior VEGF-targeted therapy, and in the
European Union for previously untreated intermediate- or poor-risk
advanced RCC. In March 2017, the FDA granted orphan drug
designation to cabozantinib for the treatment of advanced HCC. On
March 28, 2018, Ipsen announced that the European Medicines Agency
validated its application for a new indication for cabozantinib as
a treatment for previously treated advanced HCC in the European
Union. In 2016, Exelixis granted Ipsen exclusive rights for the
commercialization and further clinical development of cabozantinib
outside of the United States 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.
U.S. Important Safety Information
- Hemorrhage: Severe and fatal
hemorrhages have occurred with CABOMETYX. In two RCC studies, the
incidence of Grade ≥ 3 hemorrhagic events was 3% in
CABOMETYX-treated patients. Do not administer CABOMETYX to patients
that have or are at risk for severe hemorrhage.
- Gastrointestinal (GI) Perforations
and Fistulas: In RCC studies, fistulas were reported in 1% of
CABOMETYX-treated patients. Fatal perforations occurred in patients
treated with CABOMETYX. In RCC studies, gastrointestinal (GI)
perforations were reported in 1% of CABOMETYX-treated patients.
Monitor patients for symptoms of fistulas and perforations,
including abscess and sepsis. Discontinue CABOMETYX in patients who
experience a fistula which cannot be appropriately managed or a GI
perforation.
- Thrombotic Events: CABOMETYX
treatment results in an increased incidence of thrombotic events.
In RCC studies, venous thromboembolism occurred in 9% (including 5%
pulmonary embolism) and arterial thromboembolism occurred in 1% of
CABOMETYX-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, including hypertensive crisis.
In RCC studies, hypertension was reported in 44% (18% Grade
≥ 3) of CABOMETYX-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: In RCC studies,
diarrhea occurred in 74% of patients treated with CABOMETYX.
Grade 3 diarrhea occurred in 11% of patients treated with
CABOMETYX. 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.
- Palmar-Plantar Erythrodysesthesia
(PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE)
occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE
occurred in 8% of patients treated with CABOMETYX. Withhold
CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade
3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced
dose.
- Reversible Posterior
Leukoencephalopathy Syndrome (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 may be
associated with CABOMETYX. Advise pregnant women of the potential
risk to a fetus. Advise females of reproductive potential to use
effective contraception during CABOMETYX treatment and for 4 months
after the last dose.
- Adverse Reactions: The most
commonly reported (≥25%) adverse reactions are: diarrhea, fatigue,
nausea, decreased appetite, hypertension, PPE, weight decreased,
vomiting, dysgeusia, and stomatitis.
- Strong CYP3A4 Inhibitors: If
concomitant use with strong CYP3A4 inhibitors cannot be avoided,
reduce the CABOMETYX dosage.
- Strong CYP3A4 Inducers: If
concomitant use with strong CYP3A4 inducers cannot be avoided,
increase the CABOMETYX dosage.
- Lactation: Advise women not to
breastfeed while taking CABOMETYX and for 4 months after the final
dose.
- Hepatic Impairment: In patients
with mild to moderate hepatic impairment, reduce the CABOMETYX
dosage. CABOMETYX is not recommended for use in patients with
severe hepatic impairment.
Please see accompanying full Prescribing Information
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About Exelixis
Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially
successful, oncology-focused biotechnology company that strives to
accelerate the discovery, development and commercialization of new
medicines for difficult-to-treat cancers. Following early work in
model genetic systems, we established a broad drug discovery and
development platform that has served as the foundation for our
continued efforts to bring new cancer therapies to patients in
need. We discovered our three commercially available products,
CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib) and COTELLIC®
(cobimetinib), and have entered into partnerships with leading
pharmaceutical companies to bring these important medicines to
patients worldwide. Supported by revenues from our marketed
products and collaborations, we are committed to prudently
reinvesting in our business to maximize the potential of our
pipeline. We are supplementing our existing therapeutic assets with
targeted business development activities and internal drug
discovery - all to deliver the next generation of Exelixis
medicines and help patients recover stronger and live longer. In
July 2018, Exelixis was added to the Standard & Poor’s
(S&P) MidCap 400 index, which measures the performance of
profitable mid-sized companies. For more information about
Exelixis, please visit www.exelixis.com,
follow @ExelixisInc on Twitter or like Exelixis,
Inc. on Facebook.
Exelixis, the Exelixis logo, CABOMETYX,
COMETRIQ and COTELLIC are registered U.S. trademarks.
_________________________
References:
1 National Comprehensive Cancer Network Clinical Practice
Guidelines in Oncology. Kidney Cancer. Version 1.2019. Updated
September 4, 2018.2 National Comprehensive Cancer Network Clinical
Practice Guidelines in Oncology. Hepatobiliary Cancers. Version
3.2018. Updated August 29, 2018.3 Choueiri, T.K., et al.
Cabozantinib versus Sunitinib as Initial Targeted Therapy for
Patients with Metastatic Renal Cell Carcinoma of Poor or
Intermediate Risk: The Alliance A031203 CABOSUN Trial. Am J
Clin Oncol. 2016; 35:591-597.4 Heng D.Y., Xie W., Regan M.M., et
al. Prognostic factors for overall survival in patients with
metastatic renal cell carcinoma treated with vascular endothelial
growth factor-targeted agents: Results from a large, multicenter
study. Am J Clin Oncol. 2009; 27:5794-5799.5 American Cancer
Society: Cancer Facts and Figures 2018. Available
at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf.
Accessed September 2018.6 Jonasch, E., Gao, J., Rathmell, W.
Renal cell carcinoma. BMJ. 2014; 349:g4797.7 Decision
Resources Report: Renal Cell Carcinoma. October
2014 (internal data on file).8 Harshman, L., and Choueiri, T.
Targeting the hepatocyte growth factor/c-Met signaling pathway in
renal cell carcinoma. Cancer J. 2013; 19:316-323.9 Rankin, et
al. Direct regulation of GAS6/AXL signaling by HIF promotes renal
metastasis through SRC and MET. Proc Natl Acad Sci USA. 2014;
111:13373-13378.10 Zhou, L., Liu, X-D., Sun, M., et al. Targeting
MET and AXL overcomes resistance to sunitinib therapy in renal cell
carcinoma. Oncogene. 2016; 35:2687-2697.11 Koochekpour, et al.
The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte
growth factor/scatter factor-induced invasion and branching
morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999;
19:5902–5912.12 Takahashi, A., Sasaki, H., Kim, S., et al. Markedly
increased amounts of messenger RNAs for vascular endothelial growth
factor and placenta growth factor in renal cell carcinoma
associated with angiogenesis. Cancer Res. 1994;
54:4233-4237.13 Nakagawa, M., Emoto, A., Hanada, T., Nasu, N.,
Nomura, Y. Tubulogenesis by microvascular endothelial cells is
mediated by vascular endothelial growth factor (VEGF) in renal cell
carcinoma. Br J Urol. 1997; 79:681-687.14 Cancer Incidence and
Mortality Worldwide. Liver Cancer. International Agency for
Research on Cancer, GLOBOCAN 2012. Available
at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
Accessed September 2018.15 Mittal S, El-Serag HB. Epidemiology
of HCC: Consider the Population. Journal of Clinical
Gastroenterology. 2013. 47:S2-S6.16 Weledji E, Orock G, Ngowe M,
NsaghaD. How grim is hepatocellular carcinoma? Annals of
Medicine and Surgery. 2014. 3:71-76.
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Investors:Exelixis, Inc.Susan Hubbard, 650-837-8194EVP,
Public Affairs andInvestor
Relationsshubbard@exelixis.comorMedia:Exelixis, Inc.Lindsay
Treadway, 650-837-7522Senior Director, Public Affairs andAdvocacy
Relationsltreadway@exelixis.com
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