NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
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
Osimertinib is a small molecule tyrosine kinase receptor inhibitor and antineoplastic agent that is used in the therapy of selected forms of advanced non-small cell lung cancer (NSCLC). Osimertinib is associated with a moderate rate of serum aminotransferase elevations during therapy and rare instances of clinically apparent acute liver injury.
Background
Osimertinib (oh" sim er' ti nib) is a small molecule tyrosine kinase receptor inhibitor with potent activity against the epidermal growth factor receptor (EGFR) that is rearranged and mutated in selected cancers including approximately 5% of non-small cell lung cancer (NSCLC). The mutated, rearranged EGFR promotes unregulated cell growth and proliferation, and inhibition of its activity can result in death of cells that overexpress the receptor. Osimertinib has been found to inhibit mutated EGFR in cell culture and, in several clinical trials, was found to induce objective responses in a proportion of patients with advanced EGFR mutated (T790M) NSCLC. Osimertinib received accelerated approval for use refractory, EGFR T790M-positive NSCLC in the United States in 2015. Osimertinib is available in tablets of 40 and 80 mg under the brand name Tagrisso. The recommended initial dose is 80 mg once daily, continued until progressive disease or intolerable toxicity occurs. Side effects are common and include diarrhea, rash, dry skin and nail toxicity. Uncommon, but potentially severe side effects include interstitial lung disease, prolongation of the QTc interval, cardiomyopathy and embryo-fetal toxicity.
Hepatotoxicity
Elevations in serum aminotransferase levels are uncommon during osimertinib therapy occurring in 4% to 5% of patients and rising above 5 times the upper limit of the normal range in only 1% or less. In preregistration trials, there was a single incidence of clinically apparent liver injury attributed to osimertinib therapy, but the clinical features and relatedness to therapy were not defined. Since its approval and more widespread use, there have been no published cases of liver injury due to osimertinib.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism by which osimertinib might cause liver injury is not known. Osimertinib is metabolized by the liver predominantly by CYP 3A4 and is susceptible to drug-drug interactions with agents that induce or inhibit FYP 3A4.
Outcome and Management
Serum enzyme elevations during osimertinib therapy are uncommon, but elevations above 5 times the upper limit of normal (if confirmed) should lead to temporary discontinuation, which should be permanent if laboratory values do not improve significantly or resolve within a few weeks or if symptoms or jaundice arises. There does not appear to be cross reactivity with other EGFR inhibitors and, in some situations, switching to another protein kinase inhibitor may be appropriate.
Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors
PRODUCT INFORMATION
REPRESENTATIVE TRADE NAMES
Osimertinib – Tagrisso®
DRUG CLASS
Antineoplastic Agents
Product labeling at DailyMed, National Library of Medicine, NIH
CHEMICAL FORMULA AND STRUCTURE
DRUG | CAS REGISTRY NO. | MOLECULAR FORMULA | STRUCTURE |
---|---|---|---|
Osimertinib | 1421373-65-0 | Not available |
ANNOTATED BIBLIOGRAPHY
References updated: 01 June 2017
Abbreviations used: NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; ULN, upper limit of the normal range
- 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 such as osimertinib).
- 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 published in 2013 discusses the hepatotoxicity of crizotinib, but not osimertinib).
- Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.(Textbook of pharmacology and therapeutics).
- 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; crizotinib is listed as causing liver enzyme elevations in up to 57% of patients [≥5 times ULN in 6%] and as having been linked cases of hepatitis and fatal hepatic failure; no mention of osimertinib).
- Yang J, Ramalingam SS, Jänne PA, Cantarini M, Mitsudomi T. LBA2_PR: Osimertinib (AZD9291) in pre-treated pts with T790M-positive advanced NSCLC: updated Phase 1 (P1) and pooled Phase 2 (P2) results. J Thorac Oncol 2016; 11 (4 Suppl): S152-3.(Preliminary results in two trials of osimertinib in 474 patients with advanced NSCLC with T790M mutated EGFR revealed objective response rates of 66-71% and major side effects of rash and diarrhea).
- Noonan SA, Sachs PB, Camidge DR. Transient asymptomatic pulmonary opacities occurring during osimertinib treatment. J Thorac Oncol 2016; 11: 2253-8. [PMC free article: PMC5353353] [PubMed: 27618759](Among 20 patients with NSCLC treated with osimertinib at a single referral center, 7 [35%] developed transient, asymptomatic pulmonary opacities [by CT scan], arising within 2-43 weeks of starting and resolving within 1-11 weeks despite continuation of osimertinib).
- Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2016; 17: 1643-52. [PubMed: 27751847](Among 199 patients with NSCLC with T790 mutant EGFR positivity treated with osimertinib [80 mg daily] with an average follow up of 13 months, 70% had an objective response and adverse events included ALT elevations in 5% of patients which were above 5 times ULN in 1%, one patient stopping therapy because of liver injury, no details provided).
- Kotake M, Murakami H, Kenmotsu H, Naito T, Takahashi T. High incidence of interstitial lung disease following practical use of osimertinib in patients who had undergone immediate prior nivolumab therapy. Ann Oncol 2017; 28 (3): 669-70. [PubMed: 27993813](Among 19 Japanese patients with EGFR-T790M mutation-positive advanced NSCLC treated with osimertinib at a single Japanese institution, 4 developed interstitial lung disease within 4-12 weeks, 3 of whom had previously received nivolumab suggesting a synergistic effect in causing this adverse event; no mention of ALT elevations or liver injury).
- Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, Kim SW, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA Study Phase II Extension Component. J Clin Oncol 2017; 35 (12): 1288-96. [PubMed: 28221867](Among 201 patients with NSCLC with T790M EGFR mutation treated with osimertinib, the objective response rate was 62% and many adverse events were described including diarrhea [43%], rash [40%], and interstitial lung disease [4%], but ALT elevations and hepatotoxicity were not mentioned).
- Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, et al.; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017; 376: 629-40. [PMC free article: PMC6762027] [PubMed: 27959700](Among 419 patients with refractory EGFR T790M-poisitive NSCLC treated with osimertinib vs platinum-pemetrexed chemotherapy, the objective response rate was greater with osimertinib [71% vs 31%] and serious adverse events were less frequent [23% vs 47%], including lower rates of ALT elevations [6% vs 11%] which were rarely above 5 times ULN [1% in both]).
- Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. Osimertinib for the treatment of non-small cell lung cancer. Expert Opin Pharmacother 2017; 18: 225-31. [PubMed: 28116908](Review of the role of osimertinib in therapy of NSCLC, particularly in patients with the T790M mutation in EGFR which underlies resistance to first-generation tyrosine kinase inhibitors of EGFR; only brief mention of adverse events and no mention of ALT elevations or hepatotoxicity).
- Mamesaya N, Kenmotsu H, Katsumata M, Nakajima T, Endo M, Takahashi T. Osimertinib-induced interstitial lung disease after treatment with anti-PD1 antibody. Invest New Drugs 2017; 35: 105-7. [PMC free article: PMC5306260] [PubMed: 27599705](38 year old woman with NSCLC and T790M mutation in EGFR received osimertinib shortly after a course of nivolumab [check point inhibitor] and developed interstitial lung disease after 31 days of treated, which improved upon stopping and worsened again on restarting osimertinib; no mention of ALT elevations or liver toxicity).
- PMCPubMed Central citations
- PubChem SubstanceRelated PubChem Substances
- PubMedLinks to PubMed
- Review Ceritinib.[LiverTox: Clinical and Researc...]Review Ceritinib.. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012
- Review Alectinib.[LiverTox: Clinical and Researc...]Review Alectinib.. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012
- Review Brigatinib.[LiverTox: Clinical and Researc...]Review Brigatinib.. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012
- Long QT syndrome after using EGFR-TKIs in older patients with advanced non-small cell lung cancer.[Expert Opin Drug Saf. 2024]Long QT syndrome after using EGFR-TKIs in older patients with advanced non-small cell lung cancer.Byun JY, Han S, Qdaisat A, Park C. Expert Opin Drug Saf. 2024 Aug; 23(8):1007-1015. Epub 2023 Dec 18.
- Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study.[Lancet Oncol. 2016]Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study.Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, Satouchi M, Chu Q, Hida T, et al. Lancet Oncol. 2016 Dec; 17(12):1643-1652. Epub 2016 Oct 14.
- Osimertinib - LiverToxOsimertinib - LiverTox
- Benzodiazepine Toxicity - StatPearlsBenzodiazepine Toxicity - StatPearls
- Physiology, Bile Secretion - StatPearlsPhysiology, Bile Secretion - StatPearls
- AK4 adenylate kinase 4 [Homo sapiens]AK4 adenylate kinase 4 [Homo sapiens]Gene ID:205Gene
- 205[uid] AND (alive[prop]) (1)Gene
Your browsing activity is empty.
Activity recording is turned off.
See more...