OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Larotrectinib	1223403-58-4	C21-H22-F2-N6-O2

ANNOTATED BIBLIOGRAPHY

References updated: 15 April 2019

Abbreviations: NTKR, neurotrophic tyrosine kinase receptor.

• 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 tyrosine kinase receptor inhibitors).
• DeLeve LD. Kinase inhibitors. Gefitinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents published in 2013, before the availability of larotrectinib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2018/210861Orig1s000​_211710Orig1s000MultidisciplineR.pdf .

  (FDA website with the formal review of the safety and efficacy of larotrectinib based upon results in 176 adults and children with solid tumors and NTRK gene fusions, 45% of whom had ALT or AST elevations during therapy, which were above 5 times ULN in 6% and resulted in drug discontinuations in 2%, but no patient developed clinically apparent liver injury with jaundice).
• 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. [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 cases [6%] were attributed to antineoplastic agents, including 9 due to kinase inhibitors such as imatinib and lapatinib, but none were attributed to larotrectinib).
• DuBois SG, Laetsch TW, Federman N, Turpin BK, Albert CM, Nagasubramanian R, Anderson ME, et al. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer 2018; 124: 4241-7. [PMC free article: PMC6263791] [PubMed: 30204247]

  (5 children with advanced refractory sarcomas harboring a NTRK fusion were treated with larotrectinib, and all had an objective response and were able to undergo surgical resection, 3 with a complete response without evidence of recurrence and on no therapy 7-15 months later).
• Ziegler DS, Wong M, Mayoh C, Kumar A, Tsoli M, Mould E, Tyrrell V, et al. Brief report: Potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma. Br J Cancer 2018; 119: 693-6. [PMC free article: PMC6173734] [PubMed: 30220707]

  (A 3 year old girl with high grade glioma refractory to conventional chemotherapy was found to have a chromosomal translocation resulting in an NTRK3 fusion gene and subsequently had a dramatic clinical and radiological response to larotrectinib therapy with excellent tolerance).
• Landman Y, Ilouze M, Wein S, Neiman V, Yerushalmi R, Yakimov M, Ku N, et al. Rapid response to larotrectinib (LOXO-101) in an adult chemotherapy-naive patients with advanced triple-negative secretory breast cancer expressing ETV6-NTRK3 fusion. Clin Breast Cancer 2018; 18: e267-e270. [PubMed: 29233640]

  (37 year old woman with advanced metastatic "triple negative" breast cancer with NTRK3 fusion gene detected in tumor tissue had a dramatic clinical response to larotrectinib therapy).
• Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, Nagasubramanian R, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol 2018; 19: 705-14. [PMC free article: PMC5949072] [PubMed: 29606586]

  (Among 24 children or adolescents with advanced or metastatic solid tumors treated with larotrectinib, 14 of 15 with NTRK fusions had an objective response compared to none of those without such mutations, and side effects were mostly mild, ALT or AST elevations occurred in 42% but only one patient required discontinuation because of ALT elevations above 5 times ULN).
• Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, Nathenson M, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 2018; 378: 731-9. [PMC free article: PMC5857389] [PubMed: 29466156]

  (Among 55 children and adults with advanced or metastatic solid tumors harboring TRK fusions treated with larotrectinib, the overall response rate was 75% and adverse events were predominantly mild, with increased ALT or AST in 42%, but values above 5 times ULN in only 7% and no patient had to discontinue therapy because of treatment related adverse events).