Cabozantinib

Last updated
Cabozantinib
Cabozantinib.svg
Clinical data
Trade names Cometriq, Cabometyx, others
Other namesXL184, BMS907351, cabozantinib s-malate
AHFS/Drugs.com Monograph
MedlinePlus a613015
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding ≥99.7%
Metabolism Liver (CYP3A4-mediated)
Elimination half-life 110 hours
Excretion Feces (54%), urine (27%)
Identifiers
  • N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.221.147 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C28H24FN3O5
Molar mass 501.514 g·mol−1
3D model (JSmol)
  • COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)c2cc1OC
  • InChI=1S/C28H24FN3O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34)
  • Key:ONIQOQHATWINJY-UHFFFAOYSA-N

Cabozantinib, sold under the brand names Cometriq and Cabometyx among others, is an anti-cancer medication used to treat medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma. [9] [10] It is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and also inhibits AXL and RET. [8] [7] It was discovered and developed by Exelixis Inc.

Contents

In November 2012, cabozantinib in its capsule formulation was approved by the US Food and Drug Administration (FDA) under the name Cometriq for treating people with medullary thyroid cancer. [13] [14] The capsule form was approved in the European Union for the same purpose in 2014. [11] In April 2016, the FDA granted approval for marketing the tablet formulation (Cabometyx) as a second line treatment for kidney cancer [15] [16] and the same was approved in the European Union in September of that year. [12] The brands Cometriq and Cabometyx have different formulations and are not interchangeable. [17]

Medical uses

Cabozantinib is used in two forms. A capsule form (Cometriq) is used to treat medullary thyroid cancer [10] [8] and a tablet form (Cabometyx) is used to treat renal cell carcinoma, hepatocellular carcinoma, and differentiated thyroid carcinoma. [9] [7] [18]

Contraindications

Cabozantinib has not been tested in pregnant women; it causes harm to fetuses in rodents. Pregnant women should not take this drug, and women should not become pregnant while taking it. It is not known if cabozantinib is excreted in breast milk. [8] [7]

Adverse effects

In the US, the capsule formulation (Cometriq) carries a black box warning of the risk of holes forming in the stomach or intestines as well as formation of fistulas (tunnels between the GI tract and the skin). [10] The black box also warns against the risk of uncontrolled bleeding. [10] The tablet formulation (Cabometyx) warns of these effects as well. [9] [7]

The labels also warn of the risk of clots forming and causing heart attacks or strokes, high blood pressure including hypertensive crisis, osteonecrosis of the jaw, severe diarrhea, skin sloughing off the palms and soles, a syndrome with headaches, confusion, loss of vision, and seizures, and protein appearing in urine. [10] [9] [8] [7]

Very common adverse effects (greater than 10% of people) include decreased appetite; low calcium, potassium, phosphate, and magnesium levels; high bilirubin levels; distorted sense of taste, headache, and dizziness; high blood pressure; distorted sense of hearing, earaches and sore throat; diarrhea, nausea, constipation, vomiting, stomach pain and upset stomach, and inflammation of the mouth and lips and a burning sensation in the mouth; skin sloughing off the palms and soles, hair color changes and hair loss, rash, dry skin, and red skin; joint pain and muscle spasms; fatigue and weakness; weight loss, elevated transaminases, higher cholesterol levels, and loss of red and white blood cells. [7]

Common adverse effects (between 1% and 10% of people) include abscesses (inside the body, on the skin, and in teeth skin), pneumonia, inflamed hair follicles, fungal infections, low thyroid levels, dehydration, loss of albumin, anxiety, depression, and confusion, peripheral neuropathy, tingling, and tremor, tinnitus, atrial fibrillation, low blood pressure, blocked veins, paleness, chills, fistulas forming in the trachea and esophagus, blood clots in the lungs, and bleeding in the respiratory tract, GI perforation, bleeding in the stomach and intestines, pancreatitis, hemorrhoids, anal fissure, anal inflammation, gallstones, hard skin growths, acne, blisters, abnormal hair growth, loss of skin color and skin flaking, chest pain, blood or protein in urine, wounds that don't heal well, and facial swelling. [7]

Interactions

Cabozantinib is a substrate of CYP3A4 and multidrug resistance-associated protein 2; drugs that inhibit these enzymes will increase the half-life of cabozantinib and potentially increase its adverse effects; drugs that activate them may cause cabozantinib to be less effective. [7]

Pharmacology

Cabozantinib inhibits the following receptor tyrosine kinases: MET (hepatocyte growth factor receptor protein) and VEGFR, RET, GAS6 receptor (AXL), KIT), and Fms-like tyrosine kinase-3 (FLT3). [7] [19]

History

Cabozantinib was granted orphan drug status by the US Food and Drug Administration (FDA) in November 2010, [20] and in February 2017. [21]

Exelixis filed a new drug application with the FDA in 2012, [22] and in November 2012, cabozantinib in its capsule formulation was granted marketing approval by the FDA under the name Cometriq for treating people with medullary thyroid cancer. [13] [14] The capsule form was approved in the European Union for the same purpose in 2014. [11]

In March 2016, Exelixis licensed to Ipsen worldwide rights (outside the US, Canada, and Japan) to market cabozantinib. [23]

In April 2016, the FDA granted approval for marketing the tablet formulation as a second line treatment for kidney cancer [15] [16] and the same was approved in the European Union in September of that year. [12]

In December 2017, the FDA granted approval to cabozantinib (Cabometyx, Exelixis, Inc.) for the treatment of people with advanced renal cell carcinoma (RCC). [17] The approval was based on data from CABOSUN (NCT01835158), a randomized, open-label phase II multicenter study in 157 participants with intermediate and poor-risk previously untreated RCC. [17]

In January 2019, the FDA approved cabozantinib (Cabometyx, Exelixis, Inc.) for people with hepatocellular carcinoma who have been previously treated with sorafenib. [24] The approval was based on CELESTIAL (NCT01908426), a randomized (2:1), double-blind, placebo-controlled, multicenter trial in participants with hepatocellular carcinoma who had previously received sorafenib and had Child Pugh Class A liver impairment.

Research

Cabozantinib is being researched [25] for efficacy as a treatment for renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), cervical cancer, colorectal cancer (CRC), urothelial cancer, prostate cancer, gastric and gastroesophageal cancer, bladder cancer, melanoma, merkel cell carcinoma, brain cancers (including glioblastoma multiforme and anaplastic astrocytoma), non-small cell lung cancer (NSCLC), adrenocortical carcinoma, various sarcomas, head and neck squamous cell carcinomas (HNSCC), breast cancer, endometrial cancer, neuroendocrine cancers, and neurofibromatosis type 1. [26]

Related Research Articles

Exelixis, Inc. is a genomics-based drug discovery company located in Alameda, California, and the producer of Cometriq, a treatment approved by the U.S. Food and Drug Administration (FDA) for medullary thyroid cancer with clinical activity in several other types of metastatic cancer.

<span class="mw-page-title-main">Sorafenib</span> Chemical compound

Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer, advanced primary liver cancer, FLT3-ITD positive AML and radioactive iodine resistant advanced thyroid carcinoma.

<span class="mw-page-title-main">Sunitinib</span> Cancer medication

Sunitinib, sold under the brand name Sutent, is an anti-cancer medication. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) in January 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.

Ipsen is a French biopharmaceutical company headquartered in Paris, France, with a focus on drug development and commercialization in three therapeutic areas: oncology, rare diseases and neuroscience. Ipsen is one of the world's top 15 biopharmaceutical companies in terms of oncology sales.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Medullary thyroid cancer</span> Malignant thyroid neoplasm originating from C-cells

Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells, which produce the hormone calcitonin. Medullary tumors are the third most common of all thyroid cancers and together make up about 3% of all thyroid cancer cases. MTC was first characterized in 1959.

Ramucirumab is a fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

<span class="mw-page-title-main">Lenvatinib</span> Chemical compound

Lenvatinib, sold under the brand name Lenvima among others, is an anti-cancer medication for the treatment of certain kinds of thyroid cancer and for other cancers as well. It was developed by Eisai Co. and acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2 and VEGFR3 kinases.

Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types. By 2015 it had two US approvals for advanced cancers.

<span class="mw-page-title-main">Tivozanib</span> Medication

Tivozanib, sold under the brand name Fotivda, is a medication used for the treatment of advanced renal cell carcinoma. It is an oral VEGF receptor tyrosine kinase inhibitor.

Onyx Pharmaceuticals Inc. has been a biopharmaceutical company headquartered in South San Francisco, California. The company developed and marketed medicines for the treatment of cancer. Onyx was founded in 1992 by Kevin J. Kinsella and Frank McCormick Ph.D., FRS. McCormick served as the chief scientific officer until 1998, while Kinsella was the firm's chairman. In 2009, the company acquired Proteolix, Inc., a private biotechnology company, for $276 million in cash plus additional milestone payments. In January 2012, the company was named "the top biotechnology takeover target in 2012" through an industry survey. Onyx president and chief executive officer (CEO) N. Anthony Coles had said that Onyx liked its prospects as an independent company and was focused on bringing new therapies to patients. However, at the end of August 2013, Amgen announced it was acquiring Onyx in an agreed $10.4 billion deal.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody, more specifically a PD-1 Inhibitor, used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

Avelumab, sold under the brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma.

<span class="mw-page-title-main">Capmatinib</span> Chemical compound

Capmatinib, sold under the brand name Tabrecta, is an anticancer medication used for the treatment of metastatic non-small cell lung cancer whose tumors have a mutation that leads to the exon 14 skipping of the MET gene, which codes for the membrane receptor HGFR.

Cemiplimab, sold under the brand name Libtayo, is a monoclonal antibody medication for the treatment of squamous cell skin cancer. Cemiplimab belongs to a class of drugs that binds to the programmed death receptor-1 (PD-1), blocking the PD-1/PD-L1 pathway.

<span class="mw-page-title-main">Selpercatinib</span> Chemical compound

Selpercatinib, sold under the brand name Retevmo among others, is a medication for the treatment of cancers in people whose tumors have an alteration in a specific gene. It is taken by mouth.

Pralsetinib, sold under the brand name Gavreto, is a medication approved for RET mutation-positive medullary thyroid cancer (MTC) and RET fusion-positive differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) therapy. Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.

References

  1. ↑ "Cabozantinib Use During Pregnancy". Drugs.com. 30 March 2020. Retrieved 23 September 2020.
  2. ↑ "Cabometyx (Ipsen Pty Ltd)". Therapeutic Goods Administration (TGA). 13 January 2023. Retrieved 9 April 2023.
  3. ↑ "Cabometyx cabozantinib (as (S)-malate) 20 mg film-coated tablet bottle (283800)". Therapeutic Goods Administration (TGA). 27 May 2022. Retrieved 9 April 2023.
  4. ↑ "AusPAR: Cabozantinib". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  5. ↑ "Summary Basis of Decision (SBD) for Cabometyx". Health Canada . 23 October 2014. Retrieved 29 May 2022.
  6. ↑ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada . 14 October 2020. Retrieved 17 April 2024.
  7. 1 2 3 4 5 6 7 8 9 10 "Cabometyx 20mg, 40mg, 60mg - Summary of Product Characteristics (SmPC)". (emc). 7 October 2022. Retrieved 9 April 2023.
  8. 1 2 3 4 5 "Cometriq 20 & 80 mg hard capsules - Summary of Product Characteristics (SmPC)". (emc). 6 October 2022. Retrieved 9 April 2023.
  9. 1 2 3 4 5 "Cabometyx- cabozantinib tablet". DailyMed. 21 July 2020. Retrieved 23 September 2020.
  10. 1 2 3 4 5 6 "Cometriq- cabozantinib kit Cometriq- cabozantinib capsule". DailyMed. 11 February 2020. Retrieved 23 September 2020.
  11. 1 2 3 "Cometriq EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 23 September 2020.
  12. 1 2 3 "Cabometyx EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 23 September 2020.
  13. 1 2 "FDA approves Cometriq to treat rare type of thyroid cancer" (Press release). U.S. Food and Drug Administration (FDA). 29 November 2012. Archived from the original on July 7, 2014.
  14. 1 2 "Drug Approval Package: Cometriq (cabozantinib) Capsules NDA #203756". U.S. Food and Drug Administration (FDA). Retrieved 23 September 2020.
  15. 1 2 "Cabozantinib (Cabometyx)". U.S. Food and Drug Administration (FDA). 25 April 2016. Retrieved 23 September 2020.
  16. 1 2 "Cabometyx (cabozantinib) Tablets". U.S. Food and Drug Administration (FDA). 12 January 2018. Retrieved 23 September 2020.
  17. 1 2 3 "FDA grants regular approval to Cabometyx for first-line treatment of a". U.S. Food and Drug Administration (FDA). 19 December 2017. Retrieved 23 September 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  18. ↑ "FDA approves cabozantinib for differentiated thyroid cancer". U.S. Food and Drug Administration (FDA). 22 September 2021. Retrieved 22 September 2021.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  19. ↑ Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. (December 2011). "Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth". Molecular Cancer Therapeutics. 10 (12): 2298–2308. doi: 10.1158/1535-7163.MCT-11-0264 . PMID   21926191. S2CID   16709393.
  20. ↑ "Cabozantinib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 29 November 2010. Retrieved 11 November 2020.
  21. ↑ "Search Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 2 March 2017. Retrieved 11 November 2020.
  22. ↑ "Thyroid cancer drug cabozantinib prolongs PFS". Archived from the original on 2012-04-02. Retrieved 24 October 2011.
  23. ↑ Garde D (March 1, 2016). "Ipsen bets up to $855M on Exelixis' once-failed cancer drug". FierceBiotech.
  24. ↑ "FDA approves cabozantinib for hepatocellular carcinoma". U.S. Food and Drug Administration (FDA). 14 January 2019. Retrieved 23 September 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  25. ↑ "Search of: cabozantinib | Recruiting, Active, not recruiting, Enrolling by invitation Studies - List Results - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2021-08-09.
  26. ↑ Fisher MJ, Shih CS, Rhodes SD, Armstrong AE, Wolters PL, Dombi E, et al. (January 2021). "Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial". Nature Medicine. 27 (1): 165–173. doi:10.1038/s41591-020-01193-6. PMC   8275010 . PMID   33442015.

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