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|Exelixis Announces FDA Approval of CABOMETYX™ (Cabozantinib) Tablets for Patients with Advanced Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy|
– CABOMETYX is the first therapy to demonstrate improved overall survival, progression-free survival and objective response rate in a large, randomized phase 3 trial of patients with advanced kidney cancer –
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Renal Cell Carcinoma Fact Sheet
“With today’s announcement, patients with previously treated advanced
kidney cancer now have a new option, the first and only approved product
demonstrated to help patients live longer while also delaying the
progression of their cancer,” said
“The efficacy profile demonstrated by CABOMETYX in the METEOR trial, now
complemented by the overall survival benefit, is highly compelling,”
The approval of CABOMETYX is based on results of the phase 3 METEOR
trial, which met its primary endpoint of improving progression-free
survival. Compared with everolimus, a standard of care therapy for
second-line RCC, CABOMETYX was associated with a 42 percent reduction in
the rate of disease progression or death. Median progression-free
survival for cabozantinib was 7.4 months versus 3.8 months for
everolimus (HR=0.58, 95% CI 0.45-0.74, P<0.0001). CABOMETYX also
significantly improved the objective response rate compared with
everolimus. These data were presented at the
As announced in
The most common (frequency ≥25 percent) adverse reactions in CABOMETYX-treated patients include diarrhea, fatigue, nausea, decreased appetite, hand-foot syndrome, high blood pressure, vomiting, weight loss, and constipation. Dose reduction rates were 60 percent for CABOMETYX and 24 percent for everolimus. The rate of treatment discontinuation due to adverse reactions was low (10 percent in each arm) and consistent with that previously reported for everolimus.
Please see Important Safety Information below and full U.S. prescribing information at https://cabometyx.com/downloads/cabometyxuspi.pdf
Conference Call/Webcast at
An archived replay of the webcast will be available on the Event
Calendar page under Investors & Media at www.exelixis.com
for one year. An audio-only phone replay will be available until
About the METEOR Phase 3 Pivotal Trial
METEOR was an open-label, event-driven trial of 658 patients with
advanced renal cell carcinoma who had failed at least one prior vascular
endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor
(TKI) therapy. The primary endpoint was progression-free survival.
Secondary endpoints included overall survival and objective response
rate. The trial was conducted at approximately 200 sites in 26
countries, and enrollment was weighted toward
Patients were randomized 1:1 to receive 60 mg of CABOMETYX daily or 10 mg of everolimus daily and were stratified based on the number of prior VEGF receptor TKI therapies received and on MSKCC risk criteria. No cross-over was allowed between the study arms.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2016 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 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.1 Approximately 17,000 patients in the U.S. and 37,000 globally require second-line or later treatment.3
The majority of clear cell RCC tumors have lower than normal levels or function of the von Hippel-Lindau protein, which leads to higher levels of MET, AXL and VEGF.4,5 Higher than normal levels of these proteins can promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.6-9 MET and AXL may also provide escape pathways that drive resistance to VEGF receptor inhibitors.5,6
CABOMETYX targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.
CABOMETYX, the tablet formulation of cabozantinib, will be available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
Important Safety Information
Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-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. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-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: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. 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. Dose modification due to diarrhea occurred in 26% of patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): 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: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.
Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.
Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.
Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.
Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
Forward-Looking Statement Disclaimer
This press release contains forward-looking statements, including,
without limitation, statements related to: the therapeutic potential of
CABOMETYX; Exelixis’ commitment to making CABOMETYX available to
patients within the next couple weeks and the doses in which CABOMETYX
will be available; the eligibility for an expedited review of Exelixis’
MAA for cabozantinib in advanced RCC by the EMA; Exelixis’ commitment to
developing small molecule therapies for the treatment of cancer; and
Exelixis’ primary focus on the development and commercialization of
cabozantinib. Words such as “committed,” “will,” “eligible,” “focusing,”
or other similar expressions identify forward-looking statements, but
the absence of these words does not necessarily mean that a statement is
not forward-looking. In addition, any statements that refer to
expectations, projections or other characterizations of future events or
circumstances are forward-looking statements. These forward-looking
statements 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 coverage and reimbursement for CABOMETYX; Exelixis’
ability to judge the proper size and level of experience of the
commercialization teams required to support the launch of cabozantinib
for advanced RCC in the U.S.; Exelixis’ dependence on third-party
vendors; risks and uncertainties related to regulatory review and
approval processes and Exelixis’ compliance with applicable legal and
regulatory requirements; Exelixis’ ability to conduct clinical trials of
cabozantinib sufficient to achieve a positive completion; and other
factors discussed under the caption “Risk Factors” in Exelixis’ annual
report on Form 10-K filed with the
2. Jonasch E., Gao J., Rathmell W.K., Renal cell carcinoma. BMJ. 2014; 349:g4797.
3. Decision Resources Report: Renal Cell Carcinoma.
4. Harshman, L.C. and Choueiri, T.K., Targeting the hepatocyte growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer J. 2013; 19(4):316-23.
5. Rankin et al., Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci U S A. 2014; 111(37):13373-8.
6. Zhou L, Liu X-D, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2015 Sep 14. doi:10.1038/onc.2015.343. [Epub ahead of print].
7. 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(9):5902–5912.
8. Takahashi A, Sasaki H, Kim SJ, 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.
9. 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.