Afatinib is a tyrosine kinase receptor inhibitor that is used in the therapy of selected forms of metastatic non-small cell lung cancer. Afatinib is associated with transient elevations in serum aminotransferase levels during therapy and has been reported to cause clinically apparent acute liver injury and rare instances of death.


Afatinib (a fa' ti nib) is a small molecule tyrosine kinase receptor inhibitor with potent activity against epidermal growth factor receptor 2 (EGFR2 or ErbB1) and human epidermal growth factor receptor 2 (HER2 or ErbB2). These tyrosine kinase receptors are often mutated and over expressed in tumor tissue and cause unregulated cell growth and proliferation. Inhibition of the unregulated receptor can lead to reversal of progression of the cancer, although clinical responses are sometimes limited by the development of tumor resistance caused by further mutations in the receptor gene. In several large controlled trials, afatinib was shown to improve progression-free survival in patients with non-small cell lung cancer (NSCLC) with mutated EGFR2. Afatinib has also shown promise in therapy of some cases of advanced breast cancer. Afatinib received approval for use in the United States in 2013. Current indications are as primary therapy for metastatic NSCLC with EGFR2 mutations and as second line therapy in patients with previously treated and refractory squamous cell lung cancer. Afatinib is available in tablets of 20, 30 and 40 mg under the brand name Gilotrif. The recommended initial dose is 40 mg once daily, continued until disease progresses or intolerable toxicity occurs. Side effects are common and include diarrhea, rash, stomatitis, anorexia, nausea, dry skin, paronychia and pruritus. Uncommon, but potentially severe side effects include severe diarrhea leading to dehydration and renal failure, bullous and exfoliative skin rashes, Stevens Johnson syndrome, interstitial lung disease and embryo-fetal toxicity.


Elevations in serum aminotransferase levels are common during afatinib therapy occurring in 20% to 50% of patients, but rising above 5 times the upper limit of the normal range in only 1% to 2%. Hepatic failure is said to have occurred in 0.2% of patients and to have resulted in several fatalities. Hepatotoxicity appears to be a class effect among protein kinase inhibitors of EGFR2, although liver injury appears to be more frequent and more severe with gefitinib than with afatinib and erlotinib. Specific details of the liver injury associated with afatinib such as latency, serum enzyme pattern, clinical features and course, have not been published. Other EGFR inhibitors, such as erlotinib and gefitinib typically cause liver injury arising within days or weeks of starting therapy and presenting abruptly with hepatocellular enzyme elevations and a moderate-to-severe course. Immunoallergic and autoimmune features are not common. The rate of clinically significant liver injury and hepatic failure is increased in patients with preexisting cirrhosis or hepatic impairment due to liver tumor burden.

Likelihood score: D (possible cause of clinically apparent liver injury).

Mechanism of Injury

The abrupt and severe nature of the clinically apparent liver injury attributed to EGF receptor inhibitors suggests that it is immunologically mediated. However, the transient serum enzyme elevations that are not uncommon during therapy suggest a direct, intrinsic hepatotoxicity, perhaps caused by inhibition of critical tyrosine kinase receptors in hepatocytes. Afatinib is metabolized in the liver largely and is susceptible to drug-drug interactions with inhibitors or inducers of p-glycoprotein.

Outcome and Management

Liver injury due to afatinib varies in severity from minor, transient serum enzyme elevations to acute symptomatic hepatitis and acute liver failure. Periodic monitoring of liver tests during afatinib therapy is recommended. Serum aminotransferase 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. Corticosteroids have been used in some instances of acute liver injury due to EGFR inhibitors. Restarting therapy is usually, but not always followed by recurrence of the serum enzyme elevations. There does not appear to be cross reactivity with other tyrosine kinase receptor inhibitors and, in some situations, switching to another protein kinase inhibitor may be appropriate.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors



Afatinib – Gilotrif®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 01 June 2017

Abbreviations used: NSCLC, non-small cell lung cancer; HER-2, human epidermal growth factor receptor-2; EGFR, epidermal growth factor receptor.

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