OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Futibatinib – Lytgobi®

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
Futibatinib	1448169-71-8	C22-H22-N6-O3

ANNOTATED BIBLIOGRAPHY

References updated: 30 November 2022

Abbreviations: FGF, fibroblast growth factor; HER2, human epidermal growth factor 2 receptor.

• 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 futibatinib).
• 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 futibatinib).
• 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/2022/214801Orig1s000MultidisciplineR.pdf.

  (FDA website with product labels, letters and multidisciplinary review of the applications for futibatinib mentions that adverse events were common, led to drug discontinuation in 5% [none liver related], interruptions in 66% [10% liver related] and dose reductions in 58% [5% liver related], and ALT elevations arose in 50% of 103 treated subjects which were above 5 times ULN in 7%, but all were self-limited and there were no serious hepatic adverse events or instances of clinically apparent liver injury with jaundice).
• Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics. 2013;14:541–54. [PubMed: 23556451]

  (Review of genetic associations of serum ALT and bilirubin elevations during therapy with tyrosine kinase inhibitors focusing on lapatinib and pazopanib; futibatinib is not discussed).
• 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 futibatinib which is not discussed).
• 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).
• Bahleda R, Meric-Bernstam F, Goyal L, Tran B, He Y, Yamamiya I, Benhadji KA, et al. Phase I, first-in-human study of futibatinib, a highly selective, irreversible FGFR1-4 inhibitor in patients with advanced solid tumors. Ann Oncol. 2020;31:1405–1412. [PMC free article: PMC9743148] [PubMed: 32622884]

  (Among 86 patients with various solid tumors harboring aberrations in FGF and FGF receptor genes treated with different futibatinib dose regimens, partial responses arose in patients with cholangiocarcinoma, glioblastoma, colorectal and breast cancer, and adverse events were frequent including hyperphosphatemia [59%], constipation [34%], diarrhea [37%], nausea [29%], and ALT elevations [19%], but there were no hepatic severe adverse events or treatment related deaths).
• 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 5-10% of cancers overall, but in 10% to 20% of cholangiocarcinomas).
• Rizzo A, Ricci AD, Brandi G. Futibatinib, an investigational agent for the treatment of intrahepatic cholangiocarcinoma: evidence to date and future perspectives. Expert Opin Investig Drugs. 2021;30:317–324. [PubMed: 33054456]

  (Review of futibatinib a kinase inhibitor of FGF receptors which are commonly aberrant in cholangiocarcinoma [6-25%] and thus a strong candidate for FGF receptor kinase inhibitor therapy).
• Meric-Bernstam F, Bahleda R, Hierro C, Sanson M, Bridgewater J, Arkenau HT, Tran B, et al. Futibatinib, an irreversible FGFR1-4 inhibitor, in patients with advanced solid tumors harboring FGF/FGFR aberrations: a phase I dose-expansion study. Cancer Discov. 2022;12:402–415. [PMC free article: PMC9762334] [PubMed: 34551969]

  (Among 197 adults with various advanced solid tumors treated with futibatinib, the overall response rate was 13.7% with partial responses in various cancers including cholangiocarcinoma, gastric, urothelial, CNS, head-neck and breast cancer and the safety profile was “manageable” with ALT elevations in 64% [10% above 5 times ULN], hyperphosphatemia in 81%, diarrhea in 33%, constipation in 32%, nausea in 28%, fatigue in 25%, and hand-foot syndrome in 13%).