OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Cabozantinib	849217-68-1	C28-H24-F-N3-O5

ANNOTATED BIBLIOGRAPHY

References updated: 04 January 2017

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of proteasome inhibitors such as cabozantinib).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; cabozantinib is not discussed).
• Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.

  (Textbook of pharmacology and therapeutics).
• Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, Licitra L, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013; 31 (29): 3639-46. [PMC free article: PMC4164813] [PubMed: 24002501]

  (Among 320 patients with progressive, metastatic medullary thyroid cancer treated with cabozantinib or placebo, progression-free survival increased from 4 to 11 months with cabozantinib, but adverse side effects were common and sometimes severe including diarrhea, fatigue and hand-foot syndrome, and ALT elevations occurred in 86% of treated with 41% of controls, and above 5 times ULN occurred in 6% vs 2%, although there were no instances of "drug-induced severe liver injury").
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 [5.5%] were attributed to antineoplastic agents, of which 9 [1%] were tyrosine kinase inhibitors including imatinib [5], lapatinib [2], cediranib, and regorafenib [1 each], but none were attributed to cabozantinib).
• Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov H, Hammers TE, et al.; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373: 1814-23. [PMC free article: PMC5024539] [PubMed: 26406150]

  (Among 658 patients with progressive, metastatic renal cell carcinoma treated with cabozantinib [60 mg] vs everolimus [10 mg] daily, progression-free and overall survival were greater with cabozantinib, with which side effects were frequent including moderate-to-severe diarrhea, fatigue and hand-foot syndrome with ALT elevations in 16% vs 2% which were above 5 times ULN in 6% vs <1%; no mention of clinically apparent liver injury or serious liver related adverse events).
• Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ, et al.; METEOR investigators. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016 Jul; 17 (7): 917-27. [PubMed: 27279544]

  (Among 658 patients with advanced renal cell carcinoma treated with cabozantinib [60 mg] or everolimus [10 mg] once daily, overall survival was greater with cabozantinib [21.4 vs 18.8 months] and moderate-to-severe side effects of cabozantinib included hypertension, diarrhea, nausea, fatigue, anorexia and hand-foot syndrome, while ALT elevations occurred in 14% of patients and were above 5 times ULN in 2.4%).
• Neal JW, Dahlberg SE, Wakelee HA, Aisner SC, Bowden M, Huang Y, Carbone DP, et al.; ECOG-ACRIN 1512 Investigators. Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial. Lancet Oncol 2016; 17: 1661-71. [PMC free article: PMC5154681] [PubMed: 27825638]

  (Among 119 patients with advanced non-small cell lung cancer treated with cabozantinib or erlotinib or both, progression-free survival was greater with cabozantinib among whom AST elevations occurred in 15%, all being less than 5 times the upper limit of normal).
• Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M, Van Voorthuysen M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol 2016; 17: 1653-60. [PMC free article: PMC5143197] [PubMed: 27825636]

  (Among 26 patients with non-small cell lung cancer and RET rearrangement treated with cabozantinib [60 mg once daily], partial responses occurred in 7 patients, almost all patients had side effects, most commonly diarrhea, hand-foot syndrome, fatigue and ALT elevations [97%] which were above 5 times ULN in 8%; 19 patients [73%] required dose reductions, one [4%] for ALT elevations).
• In brief: Cabozantinib (Cabometyx) for advanced renal cell carcinoma. Med Lett Drugs Ther 2016; 58 (1499): e97. [PubMed: 27403787]

  (Concise review of the mechanism of action, clinical efficacy, safety, and costs of cabozantinib shortly after its approval for renal cell carcinoma, does not mention ALT elevations or hepatotoxicity).