Medullary Thyroid Carcinoma (MTC)


Cometriq™ (Cabozantinib) is an oral multitargeted kinase inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of progressive, metastatic medullary thyroid cancer (MTC).1 Cabozantinib is also licensed under the name Cabometyx®, which is FDA-approved for the treatment of advanced hepatocellular carcinoma and metastatic renal cell carcinoma. Cometriq and Cabometyx are not bioequivalent.2  Cometriq is also approved by the European Medicines Agency for the treatment of MTC.3 

Cabozantinib is orally available kinase inhibitor and antineoplastic agent that is used in treatment of advanced, metastatic medullary thyroid cancer and refractory renal cell carcinoma.
Credit: PubChem

Mechanism of Action and Metabolism

Cometriq is a receptor tyrosine kinase (RTK) inhibitor that targets mainly vascular endothelial growth factor receptors (VEGFRs}-1 and -2, c-MET, and RET.4,5 Other RTKs inhibited by cabozantinib include VEGFR-3, mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT-3), TIE-2 (TEK tyrosine kinase, endothelial), tropomyosin-related kinase B (TRKB), and the “anexelekto” RTK (AXL).5 

Most of cabozantinib is excreted in the feces (54%) and urine (27%).5 To a minor extent, it is metabolized by the liver via CYP3A4, and coadministration of activators of the CYP3A4 system should be avoided to prevent suboptimal serum concentrations.6 Such drugs include phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, and phenobarbital.7 

Cometriq Dosing 

Cometriq™ is available as 20- and 80-mg capsules. The recommended dose is 140 mg orally. Patients are advised not to eat for 2 hours before and 1 hour after ingestion. If the 140-mg dose cannot be tolerated because of adverse events or toxicity, the dose may be de-escalated to 120, 100, and 60 mg as needed. If at least 60 mg is not tolerated, treatment should be discontinued.7 

If patients require the concomitant use of strong CYP3A4 inhibitors, the dose should be reduced by 40 mg. For example, the starting dose should be 100 mg instead of 140 mg. Examples of strong CYP3A4 inhibitors are ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, and voriconazole.7

Get detailed prescribing information on the Cometriq monograph page at MPR.

Cometriq Efficacy

The safety, pharmacokinetics, and maximum-tolerated dose (MTD) were first established in a phase 1 dose-escalating study of 85 patients with advanced solid tumors (44% of the participants had MTC). When patients with MTC in this study were isolated, 10 of 35 patients with MTC and measurable disease (29%) had a confirmed partial response, and 15 of 37 patients with MTC (40.5%) had stable disease of at least 6 months’ duration. The overall rate of partial responses and 6-month progression-free survival was 68%.8 

Safety and efficacy were evaluated in an international, multicenter, double-blind, randomized controlled trial of 330 patients with MTC. The main measures of efficacy outcome–progression-free survival (PFS), objective response (OR), and response duration–were based on irRC-confirmed events according to modified RECIST criteria. Of the 330 patients, 48% were positive for RET mutations and 25% had received 2 or more prior systemic therapies. PFS was significantly increased in the active treatment arm, with a mean duration of 11.2 months vs 4.0 months in the placebo group (hazard ratio [HR]: 0.28; 95% CI: 0.19, 0.40; P <0.0001]). Partial responses were observed only in the Cometriq group (27%); no partial responses occurred in the placebo group. Overall survival (OS) was not significantly improved with Cometriq (26.6 vs 21.1 months; HR: 0.85; 95% CI: 0.64-1.12). However, in patients with the RET M918T mutation, OS was significantly prolonged, at 44.3 months with treatment vs 18.9 months with placebo (HR, 0.60; 95% CI, 0.38-0.94; P =0.03 [not adjusted for multiple subgroup analyses]). PFS was also significantly increased in the patients with RET M918Tpositive tumors who received Cometriq (HR: 0.15; 95% CI: 0.08-0.28; P <0.0001).9 

Adverse Events

Common adverse reactions (which occur in ≥25% of patients) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation.7

Common laboratory abnormalities (which occur in ≥25% of patients) are increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Treatment should be discontinued immediately and permanently if any of the following appear: 

  • Visceral perforation or fistula formation
  • Severe hemorrhage
  • Serious arterial thromboembolic event (eg, myocardial infarction, cerebral infarction)
  • Nephrotic syndrome
  • Malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management
  • Osteonecrosis of the jaw
  • Reversible posterior leukoencephalopathy syndrome

Special Populations7

Hepatic impairment: Cabozantinib is not recommended for patients with moderate or severe hepatic Impairment.

Renal impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with Cometriq in patients with severe renal impairment.

Pregnancy: Cabozantinib is embryotoxic. Pregnant women should be advised of risk to the fetus.

Pediatric: The drug has not been evaluated in pediatric patients. 

References 

1. 2012 Notifications. US Food and Drug Administration. Updated February 13, 2018. Accessed August 17, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/2012-notifications

2. CABOMETYX® (cabozantinib) tablets, for oral use. Exelixis. Revised January 2019. Accessed August 17, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208692s003lbl.pdf

3. Cometriq. European Medicines Agency. Updated October 6, 2021. Accessed August 17, 2021. https://www.ema.europa.eu/en/medicines/human/EPAR/cometriq

4. Cochin V, Gross-Goupil M, Ravaud A, Godbert Y, Le Moulec S. Cabozantinib: mechanism of action, efficacy and indications [in French]. Bull Cancer (Paris). 2017;104(5):393-401. doi:10.1016/j.bulcan.2017.03.013

5. Cabozantinib. PubChem. National Library of Medicine. Accessed August 17, 2021. https://pubchem.ncbi.nlm.nih.gov/compound/25102847

6. Vecchio SJD, Ellis RJ. Cabozantinib for the management of metastatic clear cell renal cell carcinoma. J Kidney Cancer VHL. 2018;5(4):1-5. doi:10.15586/jkcvhl.2018.109

7. COMETRIQTM (cabozantinib) capsules, for oral use. Exelixis. Revised November 2012. Accessed August 17, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf

8. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):2660-2666. doi:10.1200/JCO.2010.32.4145

9. Schlumberger M, Elisei R, Müller S, et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol Off J Eur Soc Med Oncol. 2017;28(11):2813-2819. doi:10.1093/annonc/mdx479

Reviewed by Harshi Dhingra, MD, on 8/30/2021.

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