OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Infigratinib – Truseltiq®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Infigratinib	872511-34-7	C26-H31-Cl2-N7-O3

ANNOTATED BIBLIOGRAPHY

References updated: 30 November 2022

Abbreviations: FGF, fibroblast growth factor.

• Zimmerman HJ. 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 inhibitors such as infigratinib).
• 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 discusses several tyrosine kinase inhibitors including imatinib, gefitinib, erlotinib and crizotinib, but not the FGF receptor inhibitors).
• 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).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2021/214622Orig1s000MultidisciplineR.pdf.

  (FDA website with product labels, letters and multidisciplinary review of the applications for infigratinib mentions that adverse events were common, led to drug discontinuation in 15% [none liver related], interruptions in 64% and dose reductions in 60%; ALT elevations arose in 51% of 108 treated subjects which were above 5 times ULN in 6%, but all were self-limited and there were no deaths from liver failure, serious hepatic adverse events or instances of clinically apparent liver injury with jaundice).
• Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013;36:491–503. [PubMed: 23620168]

  (Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013, before the availability of infigratinib which is not discussed).
• Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Brueggen J, et al. Discovery of3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011;54:7066–83. [PubMed: 21936542]

  (Description of the discovery of a series of FGF receptor inhibitors and selection of infigratinib for its in vitro and in vivo effects in inhibition of FGF receptor 1, 2 and 3 activity and inhibition of growth and proliferation of cancer cell lines that overexpressed FGF receptors).
• Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, Ojima H, et al. Fibroblast growth factor receptor tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014;59:1427–34. [PubMed: 24122810]

  (Whole transcriptome sequencing from 8 cholangiocarcinomas identified two FGF receptor fusion genes and screening of different human cancer tissues found FGF receptor fusions in 9 of 102 cholangiocarcinomas [all intrahepatic] but only 1 of 149 colorectal, 1 of 96 hepatocellular, and none of 212 gastric cancers; expression of the fusion kinases in cell cultures led to anchorage independent growth and tumorigenesis when implanted in mice).
• Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, Schellens JH, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol. 2017;35:157–165. [PMC free article: PMC6865065] [PubMed: 27870574]

  (In phase 1 dose escalating studies of infigratinib in 132 patients with advanced, refractory cancers harboring FGF receptor mutations or fusions, the maximum tolerated dose was 125 mg daily and dose defining toxicities included aminotransferase elevations; a regimen of 21 days on and 7 days off was better tolerated that continuous therapy).
• Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, Ramanathan RK, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36:276–282. [PMC free article: PMC6075847] [PubMed: 29182496]

  (Among 61 patients with advanced or metastatic cholangiocarcinoma harboring FGF receptor alterations treated with infigratinib [125 mg daily for 21 days in 28 day cycles], the objective response rate was 15%, occurring only in patients with FGF receptor fusions, while adverse events included hyperphosphatemia in 81%, fatigue 36%, stomatitis 30%, alopecia 26%, hand-foot syndrome 21%, ALT elevations 10%, and hepatic failure in 1 patient [3%]).
• Hartley IR, Miller CB, Papadakis GZ, Bergwitz C, Del Rivero J, Blau JE, Florenzano P, et al. Targeted FGFR blockade for the treatment of tumor-induced osteomalacia. N Engl J Med. 2020;383:1387–1389. [PMC free article: PMC7561341] [PubMed: 32905668]

  (66 year old man with mesenchymal tumor that produced FGF 23 resulting in hypophosphatemia and severe osteomalacia, was treated with infigratinib with a dramatic clinical and biochemical response followed by a relapse when infigratinib was stopped).
• Krook MA, Reeser JW, Ernst G, Barker H, Wilberding M, Li G, Chen HZ, et al. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. Br J Cancer. 2021;124:880–892. [PMC free article: PMC7921129] [PubMed: 33268819]

  (Review of the association of FGF receptors and cancer chemotherapeutic agents, activating mutations being found in 5% to 10% of cancers overall, but in 10% to 20% of cholangiocarcinomas).
• Kang C. Infigratinib: first approval. Drugs. 2021;81:1355–1360. [PMC free article: PMC8610935] [PubMed: 34279850]

  (Review of the chemical structure, mechanism of action, pharmacokinetics, clinical efficacy and safety of infigratinib shortly after its approval in the US, mentions ALT and AST elevations in list of adverse events but not clinically apparent hepatotoxicity or jaundice).
• Javle M, Roychowdhury S, Kelley RK, Sadeghi S, Macarulla T, Weiss KH, Waldschmidt DT, et al. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol Hepatol. 2021;6:803–815. [PubMed: 34358484]

  (Among 108 patients with advanced or metastatic cholangiocarcinoma with FGF2 fusions or rearrangements treated with infigratinib [125 mg for 21 of 28 day cycles], the objective response rate was 23% and adverse events included hyperphosphatemia [77%], stomatitis [55%], fatigue [40%], alopecia [38%], dry eyes [34%], and ALT elevations [15% with 2% above 5 times ULN], but there were no instances of clinically apparent liver injury with jaundice).
• Neuzillet C. Infigratinib in pretreated cholangiocarcinoma with FGFR2 fusions or rearrangements. Lancet Gastroenterol Hepatol. 2021;6:773–775. [PubMed: 34358483]

  (Editorial in response to Javle et al [2021] comparing results of second-line infigratinib therapy of advanced or metastatic cholangiocarcinoma [objective response rate of 23.1%] with the previous standard chemotherapy [FOLFOX: 7.7%] and the similar FGF receptor kinase inhibitor pemigatinib [35.5%]).