Gefitinib is a selective tyrosine kinase receptor inhibitor used in the therapy of non-small cell lung cancer. Gefitinib therapy is associated with transient elevations in serum aminotransferase levels and rare instances of clinically apparent acute liver injury.


Gefitinib (ge fi' ti nib) is a selective inhibitor of the tyrosine kinase receptor of epidermal growth factor (EGFR), which is often mutated and over expressed in cancer cells, particularly non-small cell lung cancer and some forms of breast cancer. The mutated EGF tyrosine kinase receptor is constitutively expressed which causes unregulated cell growth and proliferation. By inhibition of this growth factor receptor, gefitinib blocks the intracellular Ras signaling transduction cascade, which results in inhibition of the malignant cell growth. Highest rates of response to gefitinib are seen in patients with activating mutations of EGFR in the tumor tissue. Gefitinib received approval for use in the United States in 2009 for the treatment of advanced non-small cell lung cancer after failure of other therapies, but has been available in Japan since 2002. Gefitinib is available in tablets of 250 mg under the brand name Iressa. The recommended dose is 250 mg by mouth once daily, with dose modification based upon tolerance. Side effects are common and include diarrhea, nausea, vomiting, anorexia, mouth ulcers, conjunctivitis, rash, pruritus and fatigue. Uncommon serious side effects include interstitial lung disease and corneal erosions.


In large early clinical trials, elevations in serum aminotransferase levels occurred in 9% to 13% of patients treated with standard doses of gefitinib, and 2% to 4% of patients had to stop therapy because of elevations above 5 times the upper limit of normal. Serum enzyme elevations typically arise after 4 to 12 weeks of treatment with a hepatocellular pattern. Immunoallergic and autoimmune features have not been described, but rash is common in patients receiving gefitinib. Most cases of liver injury due to gefitinib in the literature have been minimally or not symptomatic, and the injury resolved within 1 to 2 months of stopping the drug. Restarting therapy was usually but not always followed by rapid recurrence of serum enzyme elevations, and corticosteroid therapy did not appear to prevent this recurrence. In some instances, lower doses were tolerated with minimal or no ALT elevations. Periodic monitoring of liver tests during therapy is recommended. Despite the frequency of serum aminotransferase elevations during gefitinib therapy, cases of clinically apparent liver injury with jaundice are rare. Cases of severe and fatal hepatotoxicity have been reported to the sponsor and monitoring of liver tests during therapy is recommended.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The cause of the liver injury due to gefitinib is unknown. Gefitinib is metabolized in the liver largely via CYP 3A4, and liver injury may be due to accumulation of a toxic or immunogenic intermediate.

Outcome and Management

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose interruption. If changes persist, are severe, or reoccur on restarting, gefitinib should be discontinued. There have been no published reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome due to gefitinib but the product label mentions severe hepatotoxicity with fatalities occurring in 0.04% of patients. Patients with liver abnormalities during gefitinib therapy generally tolerate other tyrosine kinase receptor inhibitors without recurrence of severe injury.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors


Case 1. Serum aminotransferase elevations during gefitinib therapy.

[Modified from: Takeda M, Okamoto I, Fukuoka M, Nakagawa K. Successful treatment with erlotinib after gefitinib-related severe hepatotoxicity. J Clin Oncol 2010; 28: e273-4. PubMed Citation]

A 66 year old woman with metastatic non-small cell adenocarcinoma of the lung developed serum aminotransferase elevations during therapy with gefitinib (250 mg daily). She was a nonsmoker and the lung cancer was shown to harbor a deletion in exon 19 of the epidermal growth factor receptor gene, which has been shown to confer sensitivity to inhibition by gefitinib. Serum aminotransferase levels were normal before and during the first 8 weeks of treatment, but became moderately elevated at week 13 (Table). Nevertheless, gefitinib was continued and ursodiol and glycyrrhizate [an herbal medication used in Japan as therapy of liver disease] were started. Serum enzymes gradually improved. However, 36 weeks after starting gefitinib, ALT levels rose markedly [ALT 1011 and AST 599 U/L] and gefitinib was stopped. She was taking no other medications. Abdominal ultrasound was unremarkable. Serum enzymes decreased with stopping gefitinib and 7 weeks later they were normal. Erlotinib (150 mg daily) was started and serum aminotransferase levels remained normal during long term therapy (15 weeks at the time of the report).

Key Points

Laboratory Values

* Selected values estimated from Figure 1.


Elevations in serum aminotransferase levels occur in at least 10% of patients treated with gefitinib, but they are usually mild and self-limited and rise to above 5 times the upper limit (approximately 200 U/L) in only 2% to 4% of patients, and even then may not require drug discontinuation. In this patient, the serum aminotransferase levels rose to more than 20 times the upper limit of normal which led to immediate discontinuation of therapy. Glycyrrhizate is an extract of licorice which is used in Japan as a hepatoprotective agent and usually given intravenously one to three times weekly, but its dose and regimen were not provided in this report. The authors also do not mention whether the patient was symptomatic or jaundiced and results of serum alkaline phosphatase, bilirubin and prothrombin time were not given, nor was information provided about previous liver disease, alcohol use, or results of virologic and immunologic tests to rule out other causes of liver injury. Nevertheless, the timing of presentation and prompt improvement on stopping gefitinib are convincing as was the lack of recurrence with erlotinib treatment. Monitoring of serum enzymes during gefitinib and erlotinib therapy is warranted and the agents should be discontinued if symptoms or jaundice arise or aminotransferase levels remain above 5 times the upper limit of normal in the absence of other possible etiologies.



Gefitinib – Iressa®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 06 March 2018

Abbreviations: EGFR, epidemal growth factor receptor; NSCLC, non-small cell lung cancer.

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