Cabozantinib

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Cabozantinib
Cabozantinib.svg
Systematic (IUPAC) name
N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
Clinical data
Trade names Cabometyx, Cometriq
License data
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding ≥99.7%
Metabolism Hepatic (CYP3A4-mediated)
Biological half-life 55 hours
Excretion Faeces (54%), urine (27%)
Identifiers
CAS Number 849217-68-1
ATC code L01XE26 (WHO)
ChemSpider 25948202
UNII 1C39JW444G
KEGG D10062
ChEBI CHEBI:72317 YesY
ChEMBL CHEMBL2105717
Synonyms XL184, BMS907351
Chemical data
Formula C28H24FN3O5
Molar mass 501.51 g mol

Cabozantinib, marketed under the trade name Cabometyx among others, is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has been shown to reduce tumor growth, metastasis, and angiogenesis. It was discovered and developed by Exelixis Inc.

Cabozantinib was granted orphan drug status by the U.S. Food and Drug Administration (FDA) in January 2011.[1] Cabozantinib is approved by the U.S. FDA for medullary thyroid cancer.[2] and advanced renal cell carcinoma in people who have received prior anti-angiogenic therapy.[3] It is currently undergoing clinical trials for the treatment of prostate, bladder, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, and hepatocellular cancers.

Cabozantinib will be distributed in Europe by the French pharmaceutical company Ipsen after a collaboration was reached with Exelixis in March of 2016.[4]

Approval[edit]

In October 2011, cabozantinib met its primary endpoint in a phase 3 clinical trial (EXAM) conducted by Exelixis investigating its effect on progression-free survival in medullary thyroid cancer.[5] A new drug application was submitted in the first half of 2012,[6] and on November 29, 2012 cabozantinib in its capsule formulation was granted marketing approval by the U.S. FDA under the name Cometriq for treating patients with medullary thyroid cancer.[2] Approval for its tablet formulation was granted for treating people with kidney cancer on April 25th, 2016.[7]

Grapefruit and grapefruit juice should be avoided as they may increase the concentration of the drug in the blood.[8] It is not yet known if cabozantinib is safe and effective in children.

Clinical trials[edit]

It is undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, hepatocellular and kidney cancers.[9]

Kidney cancer[edit]

A phase 3 study of cabozantinib versus everolimus in people with advanced clear renal cell carcinoma that worsened after VEGFR-target therapy, found benefit with cabozantinib.[10]

In a November 2015 vote, the National Comprehensive Cancer Network granted cabozantinib category 1 designation in advanced renal cell carcinoma for people who have received one prior VEGFR targeted tyrosine kinase inhibitor. [11] On April 25th 2016, the FDA granted approval for cabozantinib for second-line treatment of advanced clear renal cell carcinoma. [12]

Glioblastoma multiforme[edit]

In 2009 a phase II study for relapsed glioblastoma multiforme reported encouraging interim results.[13]

Prostate cancer[edit]

Positive data from clinical trials in 2011 indicate cabozantinib is beneficial in metastatic advanced prostate cancer (castration-resistant prostate cancer). 97% of patients either had stabilization or improvement in bone malignancies. The median time to disease progression was 29 weeks.[14][15]

One US trial reported in May 2011: The best results were seen in patients with liver, prostate, and ovarian cancer: 22 of 29 patients with liver cancer, 71 of 100 patients with prostate cancer, and 32 of 51 with ovarian cancer experienced either partial tumor shrinkage or stable disease. Fifty-nine out of 68 patients who had bone metastases had their metastases shrink or disappear during the trial.[16]

In 2014, COMET-1, the phase 3 pivotal trial of cabozantinib in men with metastatic castration-resistant prostate cancer whose disease progressed after treatment with docetaxel as well as abiraterone and/or enzalutamide, did not meet its primary endpoint of demonstrating a statistically significant increase in overall survival for patients treated with cabozantinib as compared to prednisone.[17] Median progression free survival did exhibit a statistically significant improvement with 5.5 months for the cabozantinib arm versus 2.8 months for the prednisone arm, but this did not translate to a statistically significant overall survival benefit at topline analysis; at that time, the median OS for the cabozantinib arm of the trial was 11.0 months versus 9.8 months for the prednisone arm.

See also[edit]

References[edit]

  1. ^ Exelixis’ XL184 Granted Orphan Drug Designation and Assigned the Generic Name Cabozantinib. Jan 2011
  2. ^ a b "FDA approves Cometriq to treat rare type of thyroid cancer". 29 November 2012. 
  3. ^ FDA Approval Announcement, April 2016
  4. ^ http://www.exelixis.com/investors-media/press-releases?cpurl=http%3A%2F%2Fir.exelixis.com/phoenix.zhtml?c=120923%26p=irol-newsArticle%26ID=2144302%26highlight=
  5. ^ "Success for the EXAM trial". Retrieved 24 October 2011. 
  6. ^ "Thyroid cancer drug cabozantinib prolongs PFS". Retrieved 24 October 2011. 
  7. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208692s000lbl.pdf
  8. ^ "Cometriq prescribing information" (PDF). Retrieved 29 November 2012. 
  9. ^ "Cabozantinib - List Results - ClinicalTrials.gov". U.S. National Institute of Health. Retrieved 25 April 2013. 
  10. ^ Choueiri, TK; Escudier, B; Powles, T; Mainwaring, PN; Rini, BI; Donskov, F; Hammers, H; Hutson, TE; Lee, JL; Peltola, K; Roth, BJ; Bjarnason, GA; Géczi, L; Keam, B; Maroto, P; Heng, DY; Schmidinger, M; Kantoff, PW; Borgman-Hagey, A; Hessel, C; Scheffold, C; Schwab, GM; Tannir, NM; Motzer, RJ; METEOR, Investigators (5 November 2015). "Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.". The New England journal of medicine 373 (19): 1814–23. PMID 26406150. 
  11. ^ http://www.nccn.org/disclosures/MinuteHandler.ashx?fileManagerId=280
  12. ^ http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=CABOMETYX
  13. ^ "A phase II study of XL184 in patients (pts) with progressive glioblastoma multiforme (GBM) in first or second relapse.". 2009. 
  14. ^ "Exelixis drug slows prostate cancer spread in trial". Reuters. 6 June 2011. 
  15. ^ Cabozantinib (XL184) Phase 2 Data Demonstrate Encouraging Clinical Activity in Patients with Castration-Resistant Prostate Cancer. Feb 2011
  16. ^ "Cabozantinib Shrinks Tumors and Bone Metastases in Prostate and Other Cancers". 31 May 2011. 
  17. ^ http://finance.yahoo.com/news/inplay-briefing-com-055139997.html#exelref

External links[edit]