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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].
Show detailsOVERVIEW
Introduction
Fruquintinib is a small molecule inhibitor of vascular endothelial growth factor (VEGF) receptors that is used in adults with metastatic, heavily pretreated colorectal cancer. Fruquintinib is associated with transient elevations in serum aminotransferase during therapy and is likely to result in clinically apparent liver injury in a proportion of patients.
Background
Fruquintinib (frue quin” tin ib) is an orally available, specific inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3 that is used in the therapy of highly refractory, metastatic colorectal cancer. VEGF receptors are frequently mutated in colorectal cancer and can account for drug resistance in therapy of metastatic colorectal cancers. Fruquintinib has activity against all three types of VEGF receptors, unlike some others which are specific for only one or two of the receptors. In two placebo controlled trials in patients with metastatic colorectal cancer who had been treated previously with multiple chemotherapeutic regimens, fruquintinib was associated with a higher rate of objective responses as well as prolongation of overall survival in comparison to placebo. Fruquintinib received accelerated approval for use in the United States in 2023. Indications were for adults with metastatic colorectal cancer after relapse or resistance to multiple, previous chemotherapies. Fruquintinib is available in capsules of 1 and 5 mg under the brand name Fruzaqla. The recommended dose regimen is 5 mg once daily in 21 day cycles every 28 days indefinitely or until intolerance or disease progression. Side effects are common with fruquintinib therapy. Common, mild-to-moderate side effects include fatigue (53%), hypertension (38%), stomatitis (31%), abdominal pain (25%), diarrhea (24%), hypothyroidism (21%), palmar-plantar erythrodysesthesia (hand-foot syndrome: 19%), proteinuria (18%), dysphonia (18%), musculoskeletal pain (16%), and arthralgia (11%). Less frequent but potentially severe adverse events include severe hypertension, hemorrhagic events, infections, gastrointestinal perforations, hand-foot syndrome, posterior reversible encephalopathy, hepatotoxicity, arterial thromboses, allergic reactions, and embryonal-fetal toxicity.
Hepatotoxicity
In the prelicensure trials of fruquintinib, liver test abnormalities were common with its use as occurs frequently with the multikinase inhibitors. In the two large placebo controlled trials, serum ALT or AST elevations arose in 39% and 44% of fruquintinib-recipients compared to 27% and 30% of placebo-recipients. Aminotransferase levels exceeded 5 times the ULN in 6% and 4% of treated vs 3% and 2% of placebo participants. Serum aminotransferase elevations with jaundice arose only in one treated patient who developed an ALT of 270 U/L, AST 131 U/L, and a total bilirubin of 4.8 mg/dL 58 days after stopping therapy. The delay in onset was interpreted as the abnormalities being unrelated to therapy. There were no life threatening episodes of liver injury and no liver related deaths among the 1101 patients in the two controlled trials. Thus, clinically apparent liver injury was not observed with fruquintinib therapy, but ALT, AST, and bilirubin elevations were common during therapy, although not always due to the fruquintinib in these patients with advanced colorectal cancer. Furthermore, several other inhibitors of VEGF receptors have been implicated in instances of acute liver injury with symptoms and jaundice (pazopanib, regorafenib, sorafenib). Since approval and more widespread use of fruquintinib, there have been no published case reports of clinically apparent liver injury with jaundice.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
Mechanism of Injury
The causes of serum enzyme elevations or liver injury from fruquintinib therapy are probably the result of direct toxicity of the multi-kinase receptor inhibition or related to hepatic metastases of the underlying colon cancer. Fruquintinib is metabolized in the liver largely via the CYP 3A4 pathway, and liver injury might be caused by production of a toxic or immunogenic intermediate of its metabolism. Because it is a substrate for CYP 3A4, fruquintinib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity.
Outcome and Management
The product label for fruquintinib recommends monitoring of liver tests before initiating therapy and periodically during treatment. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to at least temporary cessation. There is no evidence to suggest a cross reactivity in risk for adverse events, hypersensitivity, or hepatic injury between fruquintinib and other VEGF receptor inhibitors such as pazopanib, regorafenib, or sorafenib.
Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors
Other Kinase Inhibitors that Target VEGF receptors: Axitinib, Cabozantinib, Lenvatinib, Pazopanib, Regorafenib, Sorafenib, Vandetanib
PRODUCT INFORMATION
REPRESENTATIVE TRADE NAMES
Fruquintinib – Fruzaqla®
DRUG CLASS
Antineoplastic Agents
Product labeling at DailyMed, National Library of Medicine, NIH
CHEMICAL FORMULA AND STRUCTURE
| DRUG | CAS REGISTRY NO. | MOLECULAR FORMULA | STRUCTURE |
|---|---|---|---|
| Fruquintinib | 1194506-26-7 | C21-H19-N3-O5 |
|
ANNOTATED BIBLIOGRAPHY
References updated: 23 March 2025
Abbreviations: ULN, upper limit of the normal range; VEGF, vascular endothelial 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 fruquintinib).
- 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 fruquintinib).
- 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. Mult-Discipline Review. 2023. https://www
.accessdata .fda.gov/drugsatfda_docs /nda/2023/217564Orig1s000TOC.cfm (FDA review of the data on efficacy and safety of fruquintinib in support of its approval for refractory, metastatic colorectal cancer in the US, mentions that liver test abnormalities were frequent in the 911 patients treated, ALT elevations arising in 34% of fruquintinib treated subjects which were above 5 times the ULN in 5%, leading to drug withdrawal in 1%, and self-limited liver injury with jaundice in one subject which arose 2 months after stopping the drug and which was judged to be unrelated to therapy). - 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; fruquintinib 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 fruquintinib which is not discussed).
- Lu S, Chang J, Liu X, Shi J, Lu Y, Li W, Yang JJ, et al. Randomized, double-blind, placebo-controlled, multicenter phase II study of fruquintinib after two prior chemotherapy regimens in Chinese patients with advanced nonsquamous non‒small-cell lung cancer. J Clin Oncol. 2018;36:1207-1217. [PubMed: 29528793](Among 91 patients with advanced, refractory non-small cell lung cancer treated with fruquintinib or placebo, objective tumor responses and 6 month survival was higher with drug treatment [67% vs 59%]; no mention of hepatotoxicity or ALT elevations).
- Li J, Qin S, Xu RH, Shen L, Xu J, Bai Y, Yang L, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319:2486-2496. [PMC free article: PMC6583690] [PubMed: 29946728](Among 416 Chinese adults with heavily pretreated, metastatic colorectal cancer treated with fruquintinib vs placebo, the overall survival rate was higher with fruquintinib [9.3 vs 6.6 months] but severe adverse events were more common [16% vs 6%] as were ALT elevations [18% vs 9%], although elevations above 5 times ULN were uncommon in both groups [0.7% vs 1.5%] and there were no life-threatening episodes or deaths from liver injury).
- Dasari A, Lonardi S, Garcia-Carbonero R, Elez E, Yoshino T, Sobrero A, Yao J, et al.; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. [PubMed: 37331369](Among 934 adults with heavily pretreated, refractory metastatic colorectal treated with fruquintinib vs placebo, overall survival was higher with fruquintinib compared to placebo 7.4 vs 4.8 months, while adverse events arose in 63% vs 50% including ALT elevations in 10% vs 4% that were above 5 times ULN in 3% vs less than 1%; no mention of clinically apparent liver injury).
- Fruquintinib (Fruzaqla) for metastatic colorectal cancer. Med Lett Drugs Ther. 2024;66:e34-e35. [PubMed: 38412270](Concise summary of the mechanism of action, clinical efficacy, safety, and costs of fruquintinib shortly after its approval for use in heavily pretreated, metastatic colorectal cancer in the US, mentions hepatotoxicity as an adverse event and the recommendation to monitor liver tests before and periodically during therapy).
- Fusco MJ, Casak SJ, Mushti SL, Cheng J, Christmas BJ, Thompson MD, Fu W, et al. FDA approval summary: fruquintinib for the treatment of refractory metastatic colorectal cancer. Clin Cancer Res. 2024;30:3100-3104. [PMC free article: PMC11293994] [PubMed: 38809262](Summary of the data on efficacy and safety of fruquintinib that provided the basis for its approval as therapy of metastatic colorectal cancer, mentions that analysis of safety was based upon 1101 patients and that adverse events more frequent with fruquintinib included fatigue, hypertension, stomatitis, diarrhea, hypothyroidism, hand-foot syndrome, proteinuria, dysphonia, arthralgia, and musculoskeletal pain; no mention of ALT elevations or hepatotoxicity).
- PMCPubMed Central citations
- PubChem SubstanceRelated PubChem Substances
- PubMedLinks to PubMed
- Review Fruquintinib for Adult Patients With Metastatic Colorectal Cancer.[Am J Ther. 2025]Review Fruquintinib for Adult Patients With Metastatic Colorectal Cancer.Do D, Dedic C, Pinderi V, Cooper M, Ciurescu D, Dima L. Am J Ther. 2025 May-Jun 01; 32(3):e278-e283.
- Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer.[Cancer Manag Res. 2019]Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer.Zhang Y, Zou JY, Wang Z, Wang Y. Cancer Manag Res. 2019; 11:7787-7803. Epub 2019 Aug 16.
- Subgroup analysis by prior anti-VEGF or anti-EGFR target therapy in FRESCO, a randomized, double-blind, Phase III trial.[Future Oncol. 2021]Subgroup analysis by prior anti-VEGF or anti-EGFR target therapy in FRESCO, a randomized, double-blind, Phase III trial.Xu R, Qin S, Guo W, Bai Y, Deng Y, Yang L, Chen Z, Zhong H, Pan H, Shu Y, et al. Future Oncol. 2021 Apr; 17(11):1339-1350. Epub 2020 Dec 16.
- Budget impact analysis of introducing fruquintinib for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and biologics in the United States from the payer perspective.[J Med Econ. 2024]Budget impact analysis of introducing fruquintinib for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and biologics in the United States from the payer perspective.Paly VF, Li S, Khanduri P, Asfaw AA, Zou D, Hernandez L. J Med Econ. 2024 Jan-Dec; 27(1):1076-1085. Epub 2024 Aug 19.
- Review The clinical application of fruquintinib on colorectal cancer.[Expert Rev Clin Pharmacol. 2019]Review The clinical application of fruquintinib on colorectal cancer.Chen Z, Jiang L. Expert Rev Clin Pharmacol. 2019 Aug; 12(8):713-721. Epub 2019 Jun 17.
- Fruquintinib - LiverToxFruquintinib - LiverTox
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