Mechanism of Action
Tumor progression in RCC is driven by more than the VEGF pathway1-3
Functional loss of VHL upregulates proteins such as MET, AXL, VEGF, and others.1,2,4,5
Overexpression of these proteins promotes tumor angiogenesis, growth, invasiveness, and metastasis.1,3,6-8
MET and AXL may provide escape pathways that drive resistance to VEGFR inhibitors.2,3
As seen in preclinical models.
CABOMETYX® (cabozantinib) inhibits more than the VEGF pathway6,9,10
CABOMETYX® inhibits key receptors, including MET and AXL, which are involved in normal and pathologic processes such as tumor growth, invasiveness, metastasis, and drug resistance.6
*Mechanism of action shown is based on in vitro biochemical and/or cellular assays.6
AXL=Growth arrest-specific protein 6 receptor.
MET=Hepatocyte growth factor receptor.
RCC=Renal cell carcinoma.
VEGF=Vascular endothelial growth factor.
VEGFR=Vascular endothelial growth factor receptor.
References: 1. Koochekpour S, Jeffers M, Wang PH, 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. 2. Rankin EB, Fuh KC, Castellini L, 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. 3. 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]. 4. Wiesener MS, Münchenhagen PM, Berger I, et al. Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1α in clear cell renal carcinomas. Cancer Res. 2001;61:5215-5222. 5. Boysen G, Bausch-Fluck D, Thoma CR, et al. Identification and functional characterization of pVHL-dependent cell surface proteins in renal cell carcinoma. Neoplasia. 2012;14:535-546. 6. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc., 2016. 7. 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. 8. 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. 9. Roy S, Narang BK, Rastogi SK, Rawal RK. A novel multiple tyrosine-kinase targeted agent to explore the future perspectives of anti-angiogenic therapy for the treatment of multiple solid tumors: cabozantinib. Anticancer Agents Med Chem. 2015;15:37-47. 10. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298-2308. doi:10.1158/1535-7163. MCT-11-0264.
CABOMETYX® (cabozantinib) is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages have occurred
with CABOMETYX. In RCC trials, the incidence of Grade ≥3 hemorrhagic
events was 3% in CABOMETYX patients. Do not administer CABOMETYX to
patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: In
RCC trials, GI perforations were reported in 1% of CABOMETYX patients.
Fatal perforations occurred in patients treated with CABOMETYX. In RCC
studies, fistulas were reported in 1% of CABOMETYX patients. Monitor
patients for symptoms of perforations and fistulas, including abscess
and sepsis. Discontinue CABOMETYX in patients who experience a GI
perforation or a fistula that cannot be appropriately managed.
Thrombotic Events: Thrombotic events increased
with CABOMETYX. In RCC trials, venous thromboembolism occurred in
9% (including 5% pulmonary embolism) and arterial thromboembolism
occurred in 1% of CABOMETYX 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:
Treatment-emergent hypertension, including hypertensive crisis,
increased with CABOMETYX. In RCC trials, hypertension was reported
in 44% (18% Grade ≥3) of CABOMETYX 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 if there is
evidence of hypertensive crisis or for severe hypertension that
cannot be controlled with antihypertensive therapy or medical
Diarrhea: In RCC trials, diarrhea occurred in 74%
of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of
CABOMETYX 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.
Palmar-Plantar Erythrodysesthesia (PPE): In RCC
trials, PPE occurred in 42% of CABOMETYX patients. Grade 3 PPE
occurred in 8% of CABOMETYX patients. 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): RPLS, a syndrome of subcortical vasogenic edema
diagnosed by characteristic finding on MRI, occurred in the
cabozantinib clinical program. 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 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.
The most commonly reported (≥25%) adverse reactions were: 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
Strong CYP3A4 Inducers: If concomitant use with
strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX
USE IN SPECIFIC POPULATIONS
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
Please see accompanying full Prescribing Information
IMDC=International Metastatic Renal Cell Carcinoma Database Consortium;
TKI=tyrosine kinase inhibitor.
Reference: 1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis Inc., 2017.