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Cabozantinib Success Stories On Treating Caner
Cabozantinib Success Stories On Treating Caner.................................................................................. 1 CabozantinibDescription................................................................................................................... 2 CabozantinibMechanismOfAction.....................................................................................................2 CabozantinibSideEffects................................................................................................................... 3 LatestDevelopmentOfCabozantinib.................................................................................................. 4 CabozantinibTreatmentSuccessStories...............................................................................................5 Story1:CabozantinibTreatFirst-LineTreatmentofAdvancedRenalCellCarcinoma.............................. 5 Story2:CabozantinibTreatMedullaryThyroidCancer.....................................................................7 Story3:CabozantinibTreatHepatocellularCarcinoma.....................................................................8 Summary........................................................................................................................................9 Reference............................................................................................................................... 9
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Cabozantinib Description Cabozantinib(CAS:849217-68-1) is used to treat advanced kidney cancer, sometimes in combination with another medicine called nivolumab. Cabozantinib is also used to treat liver cancer in people who have been previously treated with sorafenib. Cabozantinib is used to treat thyroid cancer that has spread to other parts of the body. Cabozantinib may also be used for purposes not listed in this medication guide.
Cabozantinib Mechanism Of Action Targeted therapy is the result of about 100 years of research dedicated to understanding the differences between cancer cells and normal cells. To date, cancer treatment has focused primarily on killing rapidly dividing cells because one feature of cancer cells is that they divide rapidly. Unfortunately, some of our normal cells divide rapidly too, causing multiple side effects. Targeted therapy is about identifying other features of cancer cells. Scientists look for specific differences in the cancer cells and the normal cells. This information is used to create a targeted therapy to attack the cancer cells without damaging the normal cells, thus leading to fewer side effects. Each type of targeted therapy works a little bit differently but all interfere with the ability of the cancer cell to grow, divide, repair and/or communicate with other cells. There are different types of targeted therapies, defined in three broad categories. Some targeted therapies focus on the internal components and function of the cancer cell. The targeted therapies use small molecules that can get into the cell and disrupt the function of the cells, causing them to die. There are several types of targeted therapy that focus on the inner parts of the cells. Other targeted therapies target receptors that are on the outside of the cell. Therapies that target receptors are also known as monoclonal antibodies. Antiangiogenesis inhibitors target the blood vessels that supply oxygen to the cells, ultimately causing the cells to starve. Cabozantinib is a targeted therapy that targets and binds to the tyrosine kinase receptors and inhibits the activity of multiple tyrosine kinases, including RET, MET, and VEGF on the surface of the cell. By binding to these receptors, cabozantinib blocks important pathways that promote cell division. Research continues to identify which cancers may be best treated with targeted therapies and to identify additional targets for more types of cancer. 2
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Cabozantinib Side Effects Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Cabozantinib may cause a perforation (a hole or tear) or a fistula (an abnormal passageway) within your stomach or intestines. Call your doctor if you have severe stomach pain, or if you feel like you are choking and gagging when you eat or drink. Call your doctor at once if you have: ▪ Severe headache, blurred vision, pounding in your neck or ears; ▪ Vomiting, diarrhea, or constipation that are severe and ongoing; ▪ Swelling in your hands, arms, legs, or feet; ▪ Easy bruising or bleeding (nosebleeds, bleeding gums, heavy menstrual bleeding, or any bleeding that will not stop); ▪ Bloody or tarry stools, cough with bloody mucus or vomit that looks like coffee grounds; ▪ Jaundice (yellowing of the skin or eyes); ▪ Pain, blisters, bleeding, or severe rash in the palms of your hands or the soles of your feet; ▪ Confusion, thinking problems, weakness, vision changes, seizure; ▪ A light-headed feeling, like you might pass out; ▪ Jaw pain or numbness, red or swollen gums, loose teeth, or slow healing after dental work; ▪ Low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough, trouble breathing; ▪ Adrenal gland problems–nausea, vomiting, extreme tiredness, dizziness, weakness, fainting; or ▪ Signs of a stroke or blood clot–sudden numbness or weakness on one side of your body, problems with vision or balance, trouble speaking or understanding what is said to you, chest pain, trouble breathing, swelling or pain in an arm or leg. Your future doses of cabozantinib may be delayed or permanently discontinued if you have certain side effects.
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Common side effects may include: ▪ Stomach pain, nausea, vomiting, loss of appetite, diarrhea, constipation; ▪ Pain, redness, swelling, or sores in your mouth or throat; ▪ Trouble speaking, changes in taste; ▪ Cold symptoms such as stuffy nose, sneezing, sore throat, cough; ▪ rash; ▪ Pain in your muscles, bones, and joints; ▪ Abnormal liver function tests or other blood tests; ▪ Feeling tired; ▪ Weight loss; or ▪ Hair color turning lighter. This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Latest Development Of Cabozantinib Cabozantinib was granted orphan drug status by the U.S. Food and Drug Administration (FDA) in November 2010 and in February 2017. Exelixis filed a new drug application with the FDA in the first half of 2012 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.The capsule form was approved in the European Union for the same purpose in 2014. In March 2016 Exelixis licensed to Ipsen worldwide rights (outside the US, Canada, and Japan) to market cabozantinib. Exelixis’ Phase III trial results of testing the drug in renal cancer published in the NEJM in 2015. In April 2016 the FDA granted approval for marketing the tablet formulation as a second line treatment for kidney cancer and the same was approved in the European Union in September of that year. In December 2017, the FDA granted approval to cabozantinib (Cabometyx, Exelixis, Inc.) for treatment of people with advanced renal cell carcinoma (RCC). The approval was based on data from CABOSUN (NCT01835158), a randomized, open-label phase II 4
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multicenter study in 157 participants with intermediate and poor-risk previously untreated RCC. In January 2019, the FDA approved cabozantinib (Cabometyx, Exelixis, Inc.) for people with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. The approval was based on CELESTIAL (NCT01908426), a randomized (2:1), double-blind, placebo-controlled, multicenter trial in participants with HCC who had previously received sorafenib and had Child Pugh Class A liver impairment. Cabozantinib is being researched for efficacy as a treatment for neurofibromatosis type 1. The Food and Drug Administration (FDA) recently approved cabozantinib for the treatment of hepatocellular carcinoma in patients who previously received sorafenib. Cabozantinib is an oral tyrosine kinases inhibitor of MET, VEGFR, and AXL.Receptor tyrosine kinases play important roles in both normal cellular function and pathologic processes, including oncogenesis, metastasis, tumor angiogenesis, and tumor microenvironment maintenance. The FDA first approved cabozantinib for treatment of medullary thyroid cancer. Later, the FDA approved its use in renal cell carcinoma.
Cabozantinib Treatment Success Stories Story 1: Cabozantinib Treat First-Line Treatment of Advanced Renal Cell Carcinoma On December 19, 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to cabozantinib (Cabometyx) for treatment of patients with advanced renal cell carcinoma (RCC). The FDA previously approved cabozantinib in 2016 for treatment of patients with advanced RCC who have received prior antiangiogenic therapy. Today’s approval
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provides for treatment in the first-line
setting. This approval was based on data from the CABOSUN trial, a randomized, open-label phase II multicenter study in 157 patients with intermediate- and poor-risk previously untreated RCC. Patients received cabozantinib (n = 79) 60 mg orally daily or sunitinib (Sutent) (n = 78) 50 mg orally daily (4 weeks on treatment followed by 2 weeks off) until disease progression or unacceptable toxicity. Estimated median progression-free survival (as assessed by blinded independent radiology review committee) for patients taking cabozantinib was 8.6 months (95% confidence interval [CI] = 6.8–14.0) compared with 5.3 months (95% CI = 3.0–8.2) for patients taking sunitinib (hazard ratio = 0.48; 95% CI = 0.31–0.74; P = .0008). The most commonly reported (≥ 25%) adverse reactions in the cabozantinib clinical program are diarrhea, fatigue, nausea, decreased appetite, hypertension, palmar-plantar erythrodysesthesia, weight loss, vomiting, dysgeusia, and stomatitis. The most frequent grade 3–4 adverse reactions (≥ 5%) in patients treated with cabozantinib on CABOSUN were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, ALT increase, decreased appetite, stomatitis, pain, hypotension, and syncope. The recommended dose of cabozantinib is 60 mg orally, once daily.
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Cabozantinib is also approved for the treatment of medullary thyroid cancer and is marketed under the trade name Cometriq. Cometriq and Cabometyx have different formulations and are not interchangeable.
Story 2: Cabozantinib Treat Medullary Thyroid Cancer The FDA approved cabozantinib (Cometriq) to treat metastatic medullary thyroid cancer (MTC) in November 2012. It was based on results from an international, multicenter, randomized, double-blind, controlled trial including 330 subjects. Participants needed to exhibit progressive disease within 14 months before study entry, which was confirmed via an independent radiology review committee or the treating physician. Patients were randomized to receive either cabozantinib 140 mg or placebo orally once daily until progressive disease or intolerable toxicity. Randomization was stratified according to age < 65 years vs > 65 years and previous utilization of a tyrosine kinase
inhibitor. Primary endpoints were progression-free survival (PFS), objective response (OR), and response duration employing modified RECIST criteria. Patients in the cabozantinib group had prolonged PFS compared to those receiving placebo (P < .0001). Specifically, median PFS in the cabozantinib arm was 11.2 months and median PFS in the placebo arm was 4.0 months. Only patients taking cabozantinib experienced a partial response (27% vs 0; P < .0001). Furthermore, the median duration of OR was 14.7 months for those treated with the drug. No significant differences in overall survival were observed between arms.
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In a 2019 meta- and economic analysis evaluating the utility of cabozantinib and vandetanib in patients of England’s National Health Service, Tappenden et al. Concluded. “The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs [incremental cost-effectiveness ratios] for cabozantinib and vandetanib are > £138,000 per QALY (quality-adjusted life year) gained. Within the restricted EU (European Union)-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.”
Story 3: Cabozantinib Treat Hepatocellular Carcinoma In January 2019, the FDA approved cabozantinib tablets for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. The approval was based on results from the CELESTIAL trial. In the randomized (2:1), double-blind, placebo-controlled, multicenter trial, patients were randomized to cabozantinib 60 mg orally once daily (n=470) or placebo (n=237) until the time of disease progression or unacceptable
toxicity. The primary endpoint was OS. PFS and ORR , assessed by investigators using RECIST 1.1, were also measured. Cabozantinib use was associated with a median OS of 10.2 months (95% CI: 9.1-12.0) vs 8 months (95% CI: 6.8-9.4) for those receiving placebo (HR 0.76; 95% CI: 0.63, 0.92; P = .0049). Median PFS was 5.2 months (4.0-5.5) in the cabozantinib arm compared with 1.9 months (1.9-1.9) in the placebo arm (HR 0.44; 95%
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CI, 0.36, 0.52; P < .001). The ORR was 4% (95% CI, 2.3, 6.0) in those taking cabozantinib vs 0.4% (95% CI, 0.0, 2.3) in those taking placebo. Grade 3 or 4 adverse events were higher in patients taking cabozantinib (68%) than in those taking placebo (36%). Authors of the CELESTIAL trial concluded with the following: “Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group.”
Summary Cabozantinib is a tyrosine kinase inhibitor used to treat advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer. Cabozantinib was first approved in 2012 and is a non-specific tyrosine kinase inhibitor. It was initially approved in the US under the brand name Cometriq, which is indicated for the treatment of metastatic medullary thyroid cancer.In 2016, a capsule formulation (Cabometyx) was approved for the treatment of advanced renal cell carcinoma, and this same formulation gained additional approval in both the US and Canada in 2019 for the treatment of hepatocellular carcinoma in previously treated patients.
Reference [1] Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17: 917–27. [2] Tappenden P, Carroll C, Hamilton J, et al. Cabozantinib and vandetanib for unresectable locally advanced or metastatic medullary thyroid cancer: a systematic review and economic model. Health Technol Assess. 2019;23:1-144. [3] George DJ, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib for untreated patients with advanced renal cell carcinoma of intermediate or poor risk: subgroup analysis of the Alliance A031203 CABOSUN trial. Oncologist. 2019;24:1–5. [4] Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Muller T, Ratain MJ, Salgia R: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in 9
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patients with medullary thyroid cancer. J Clin Oncol. 2011 Jul 1;29(19):2660-6. doi: 10.1200/JCO.2010.32.4145. Epub 2011 May 23. [5] Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63. [6] US Food and Drug Administration. FDA approves cabozantinib for hepatocellular carcinoma. Available at: https://www.fda.gov/drugs/fda-approves-cabozantinib-hepatocellular-carcinoma Accessed August 28, 2019. [7] Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011 Dec;10(12):2298-308. doi: 10.1158/1535-7163.MCT-11-0264. Epub 2011 Sep 16. [8] “Thyroid cancer drug cabozantinib prolongs PFS”. Archived from the original on 2012-04-02. Retrieved 24 October 2011. [9] “Cabozantinib Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 29 November 2010. Retrieved 11 November 2020.
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