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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-.

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LiverTox®: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Repotrectinib

Last Update: April 7, 2025.

OVERVIEW

Introduction

Repotrectinib is a small molecule inhibitor of the proto-oncogene tyrosine-protein kinase ROS1 and of tropomyosin receptor tyrosine kinases (TRK-A, -B and -C) and is used to treat adults with non-small cell lung cancer. Repotrectinib is associated with a moderate rate of mild transient elevations in serum aminotransferase levels during therapy but has not been linked to episodes of clinically apparent liver injury with jaundice.

Background

Repotrectinib (re poe trek’ ti nib) is a small molecule inhibitor of the proto-oncogene tyrosine-protein kinase ROS1 and of tropomyosin receptor tyrosine kinases (TRKA, B and C) and is used to treat adults with non-small cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer deaths in the United States and NSCLC accounts for approximately 85% of lung cancer. ROS1 mutations and rearrangements are found in up to 2% of NSCLC cases and is associated with poor survival. The function of ROS1 is not well defined; it appears to be an oncogene and to act through downstream activation of ERK and MAPK pathways. Antineoplastic agents that specifically target ROS1 include crizotinib, entrectinib, and repotrectinib. Repotrectinib has potent activity against both wild type and mutant rearranged ROS1 as well as against several TRK mutants often found in combination with ROS1. In a large, open label study of repotrectinib in patients with ROS1 positive NSCLC, the objective response rate was 79% in tyrosine kinase naïve patients and 38% in those with previous tyrosine kinase therapy. Importantly, responses were seen in some patients with central nervous system metastases. Based upon these results, repotrectinib was approved as therapy for locally advanced or metastatic ROS1-positive NSCLC in 2023. Repotrectinib is available in capsules of 40 and 160 mg under the brand name Augtyro. The recommended dose is 160 mg once daily for 14 days followed by 160 mg twice daily continued until unacceptable tolerance or disease progression. In 2024, indications for repotrectinib were extended to solid tumors that have neurotrophic tyrosine kinase receptor gene fusion and that are locally advanced or metastatic and not amenable to surgical resection. Side effects of repotrectinib are common and include dizziness, dysgeusia, peripheral neuropathy, constipation, nausea, fatigue, muscular weakness, dyspnea, ataxia and cognitive impairment. Less frequent but potentially severe adverse events include severe central nervous system effects, interstitial lung disease, hepatotoxicity, myalgia and CPK elevations, hyperuricemia, skeletal fractures, and embryo-fetal toxicity.

Hepatotoxicity

In the prelicensure trials of repotrectinib as therapy of ROS1-positive NSCLC, liver test abnormalities were frequent but usually mild-to-moderate in severity and self-limited in duration. ALT elevations arose in 34% and AST in 40% and were above 5 times the ULN in 3.1% and 1.9% of the 264 patients treated in the major registration trial. The median time to onset of aminotransferase elevations was 15 days (range 1 day to 1 year). Dose interruptions for ALT abnormalities were done in 1.1% of patients but permanent discontinuations were rare. There were no enzyme elevations with jaundice or symptoms and no life threatening or fatal instances of liver injury. Since approval and clinically availability of repotrectinib, there have been no published case reports of clinically apparent liver injury with jaundice, but clinical experience with its use has been limited.

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 repotrectinib therapy are possibly due to direct toxicity of the ROS1 pathway inhibition, but some are likely related to hepatic metastases from the underlying advanced lung cancer. Repotrectinib is metabolized in the liver largely via CYP 3A4 and is susceptible to drug-drug interactions. Repotrectinib is a CYP 3A inducer that can alter the metabolism of CYP 3A substrates. Furthermore, concomitant use of agents that induce or inhibit CYP 3A4 activity should be avoided during therapy with repotrectinib.

Outcome and Management

The product label for repotrectinib recommends monitoring of liver tests before therapy, every 2 weeks during the first month, and every month thereafter and as clinically indicated. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to discontinuation until levels fall to less than twice ULN. There is little information on cross reactivity in risk for adverse events, hypersensitivity, or hepatic injury between repotrectinib and other ROS1 inhibitors such as crizotinib and entrectinib. Switching to those agents should be done with caution and with close monitoring.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

Other ROS1 Inhibitors: Crizotinib, Entrectinib

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Repotrectinib – Augtyro®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Repotrectinib 1802220-02-5 C18-H18-FN5-O2 image 348351330 in the ncbi pubchem database

ANNOTATED BIBLIOGRAPHY

References updated: 7 April 2025

Abbreviations: NSCLC, non-small cell lung cancer; ROS1, proto-oncogene tyrosine-protein kinase; ULN, upper limit of the normal range.

  • 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 repotrectinib).
  • 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 repotrectinib).
  • 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. Multi-Discipline Review. 2023. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2023/218213Orig1s000MultidisciplineR.pdf
    (FDA review of the data on efficacy and safety of repotrectinib in support of its approval for ROS1-positive NSCLC in the US, mentions that liver test abnormalities were frequent in the 264 patients who received repotrectinib in the large open-label, prelicensure clinical trial, ALT elevations arising in 34%, AST in 40%, Alk P in 26%, and rising to above 5 times the upper limit of normal (ULN) in 3.1%, 1.9%, and 2.3% of patients, leading to dose interruptions in 2.8%, but discontinuation due to liver test abnormalities were rare and there were no instances of drug induced liver injury or enzyme elevations accompanied by 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; repotrectinib 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 repotrectinib which is not discussed).
  • Drilon A, Camidge DR, Lin JJ, Kim SW, Solomon BJ, Dziadziuszko R, Besse B, et al; TRIDENT-1 Investigators. Repotrectinib in ROS1 fusion-positive non-small-cell lung cancer. N Engl J Med. 2024;390: 118-131. [PMC free article: PMC11702311] [PubMed: 38197815]
    (Among 520 adults with locally advanced or metastatic ROS1-positive NSCLC, 103 were treated in a phase 1 dose-finding study and 416 in a phase 2 optimal dose trial, and of 127 with ROS1 fusion rearrangements, the objective response rate was 79% in tyrosine kinase inhibitor (TKI) naïve patients with a median progression-free survival of 36 months, and was 38% in those with previous TKI therapy with a median progression-free survival of 9 months; 99% of patients had at least one adverse event, 35% had a serious event, 50% had dose interruptions, 7% had discontinuations for adverse events, and 23% had ALT elevations which were greater than 5 times ULN in 2%; no mention of hepatic serious adverse events or hepatotoxicity).
  • Dhillon S. Repotrectinib: first approval. Drugs. 2024;84:239-246. [PubMed: 38279972]
    (Review of the mechanism of action, history of development, pharmacology, clinical efficacy, and safety of repotrectinib shortly after its first approval in the US for advanced or metastatic ROS1-positive NSCLC, mentions it has a “manageable tolerability profile” and the many common adverse events including elevations in GGT [48%] and AST [40%] and elevations of ALT above 5 times ULN [3%], but does not mention hepatotoxicity or occurrence of serious, life-threatening, or fatal liver injury).
  • Repotrectinib (Augtyro) for non-small cell lung cancer. Med Lett Drugs Ther. 2024;66:e36-e37. [PubMed: 38412271]
    (Concise review of the mechanism of action, clinical efficacy, safety, and costs of repotrectinib, mentions hepatotoxicity and that “liver function should be assessed every 2 weeks during the first month of treatment and periodically thereafter”).
  • Barbato MI, Bradford D, Ren Y, Aungst SL, Miller CP, Pan L, Zirkelbach JF, et al. FDA approval summary: repotrectinib for locally advanced or metastatic ROS1-positive non-small cell lung cancer. Clin Cancer Res. 2024;30:3364-3370. [PMC free article: PMC11326972] [PubMed: 38875108]
    (Review of the data on efficacy and safety of repotrectinib that supported its FDA approval as therapy for locally advanced or metastatic ROS1-positive NSCLC, mentions that serious adverse reactions occurred in 33% and fatal events in 4.2% of the 264 patients in the safety population; no mention of ALT elevations or hepatotoxicity).
  • Desilets A, Repetto M, Yang SR, Drilon A. Targeting ROS1 rearrangements in non-small cell lung cancer: Current insights and future directions. Cancer. 2025;131 Suppl 1: e35784. [PMC free article: PMC12551656] [PubMed: 40171848]
    (Review of the role of ROS1 mutant rearrangements in NSCLC accounting for 1-2% of cases, responding to tyrosine kinase inhibitors targeting ROS1 but with resistant mutations arising after use of first generation inhibitors; ROS1 being an evolutionarily conserved transmembrane protein with an unknown ligand and unclear physiological function, but perhaps by signaling via Ras/Raf/ERK as well as MAPK, PIK3, AKT, mTOR, or STAT3 pathways).

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