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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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Erlotinib

Last Update: June 28, 2018.

OVERVIEW

Introduction

Erlotinib is a tyrosine kinase receptor inhibitor that is used in the therapy of advanced or metastatic pancreatic or non-small cell lung cancer. Erlotinib therapy is associated with transient elevations in serum aminotransferase levels during therapy and rare instances of clinically apparent acute liver injury.

Background

Erlotinib (er loe' ti nib) is a selective inhibitor of several tyrosine kinase receptors which are associated with tumor growth and angiogenesis. The tyrosine kinase receptors are often mutated and over expressed in tumor tissue and cause unregulated cell growth and proliferation. Erlotinib is one of several tyrosine kinase inhibitors that have been introduced into cancer chemotherapy and are specially directed at molecular abnormalities that occur in cancer cells. Inhibition of the 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. Erlotinib has special activity against the human epidermal growth factor (EGF) tyrosine kinase receptors HER-1 and EGFR which are found in several forms of cancer. Erlotinib received approval for use in the United States in 2004. Current indications are for locally advanced, unresectable or metastatic pancreatic cancer in combination with gemcitabine and for locally advanced or metastatic non-small-cell lung cancer as a first line treatment in patients with specific, erlotinib sensitive mutations in EGFR or after failure of at least one chemotherapy regimen. Erlotinib is available in tablets of 25, 100 and 150 mg under the brand name Tarceva, and the typical dose is either 100 mg (pancreatic cancer) or 150 mg (lung cancer) once daily by mouth, continued until disease progresses or intolerable toxicity occurs. Side effects include fatigue, rash, diarrhea, anorexia, skin discoloration, hand-foot syndrome, edema, muscle cramps, arthralgias, headache, abdominal discomfort, anemia, cough, and pruritus. Uncommon, but potentially severe side effects include heart failure, interstitial lung disease, gastrointestinal perforation, pancreatitis, renal failure, severe skin reactions and embryo-fetal toxicity.

Hepatotoxicity

Elevations in serum aminotransferase levels are common during erlotinib therapy of pancreatic and lung cancers, and values above 5 times the upper limit of normal occur in at least 10% of patients. Similar rates of ALT elevations, however, can occur with comparable antineoplastic regimens. The abnormalities are usually asymptomatic and self-limited, but may require dose adjustment or discontinuation (Case 1). In addition, there have been rare reports of clinically apparent liver injury attributed to erlotinib therapy. The time to onset is typically within days or weeks of starting therapy, and the liver injury can be severe, there being at least a dozen fatal instances reported in the literature. The onset of injury can be abrupt and the pattern of serum enzyme elevations is usually hepatocellular (Case 2). Immunoallergic features (rash, fever and eosinophilia) are not common and autoantibody formation has not been reported. Routine monitoring of liver tests during therapy is recommended. 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: B (likely but uncommon cause of clinically apparent liver injury).

Mechanism of Injury

The abrupt and severe nature of the clinically apparent liver injury attributed to erlotinib suggests that it is immunologically mediated. In contrast, the transient serum enzyme elevations that occur during therapy may have a different cause and be the result of direct toxicity. Erlotinib is metabolized in the liver through the cytochrome P450 system (largely CYP 3A4).

Outcome and Management

Liver injury due to erlotinib varies in severity from minor, transient serum enzyme elevations to acute symptomatic hepatitis and acute liver failure. Monitoring of routine liver tests before starting and at regular intervals during erlotinib 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 3 weeks. Restarting therapy is usually, but not always followed by recurrence of the serum enzyme elevations. There appears to be partial cross sensitivity to liver injury among similar tyrosine kinase receptor inhibitors and, in some situations, switching to another with careful monitoring may be appropriate. Cases of acute liver failure have occurred in patients receiving erlotinib and are challenging as these patients rarely qualify for liver transplantation. Patients with acute liver failure due to erlotinib have been treated with corticosteroids, but there benefit remains unproven. In using this medication, other potentially hepatotoxic agents should be avoided (such as high doses of acetaminophen).

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

CASE REPORTS

Case 1. Serum enzyme elevations due to erlotinib therapy.

[Modified from: Saif MW. Erlotinib-induced acute hepatitis in a patient with pancreatic cancer. Clin Adv Hematol Oncol 2008; 6: 191-9. PubMed Citation]

A 52 year old man with locally advanced pancreatic cancer developed rising serum enzyme elevations 7 weeks after starting erlotinib therapy. He had presented initially with jaundice and was found to have a mass in the head of the pancreas that was shown to be adenocarcinoma by thin needle aspiration. He was treated initially with biliary stenting followed by gemcitabine, oxaliplatin and external beam radiation. Because of unresectability and oxaliplatin induced neuropathy, he was then treated with gemcitabine and erlotinib. His baseline liver tests were mildly abnormal and he was monitored carefully during erlotinib therapy. Seven weeks after stating erlotinib, serum ALT and alkaline phosphatase levels began to rise (Table). He was maintained on erlotinib and gemcitabine and monitored more carefully. Eleven weeks into treatment, however, serum enzymes had risen to more than 5 times the upper limit of the normal range. Tests for hepatitis A, B and C were negative and he was taking no other medications. Abdominal imaging showed no interval change in the pancreatic mass and no evidence of extrahepatic obstruction. Erlotinib was stopped and he was maintained on gemcitabine alone. Liver enzymes decreased to baseline values within the following 8 weeks.

Key Points

Medication:Erlotinib (100 mg daily)
Pattern:Cholestatic (R=1.9)
Severity:1+ (serum enzyme elevations only)
Latency:7-13 weeks
Recovery:8 weeks
Other medications:Gemcitabine

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
- 6 months39850.5
0531760.5Erlotinib started
4 weeks411440.3
6 weeks761450.5
9 weeks701620.4CT scan: no change
11 weeks1312830.3
13 weeks01933760.7Erlotinib stopped
14 weeks1 weeks1993460.3
15 weeks2 weeks2884910.4
16 weeks3 weeks1574440.2
19 weeks6 weeks852590.3
22 weeks9 weeks621760.4
Normal Values <35 <130 <1.2

Comment

The patient developed gradual increases in serum aminotransferase and alkaline phosphatase levels while being treated with erlotinib, and therapy was discontinued when ALT levels reached 5 times the upper limit of the normal range (considered Grade 3 toxicity). The severity of the liver injury, however, should be considered mild, as there was no jaundice and apparently no symptoms of hepatic injury. Because the patient had pancreatic cancer, the abnormalities could have indicated progressive malignant disease, particularly because of the cholestatic pattern of the enzymes and their gradual rise. However, imaging showed no evidence of an increase in the size of the pancreatic mass or evidence of biliary obstruction, and the abnormalities resolved once erlotinib was stopped. Grade 3 elevations in serum ALT levels occur in 5% to 10% of patients treated with erlotinib and gemcitabine, and this rate is only slightly higher than occurs with gemcitabine alone.

Case 2. Acute liver failure and death due to erlotinib therapy.

[Modified from: Liu W, Makrauer FL, Qamar AA, Jänne PA, Odze RD. Fulminant hepatic failure secondary to erlotinib. Clin Gastroenterol Hepatol 2007; 5: 917-20. PubMed Citation]

A 57 year old woman with metastatic non-small cell lung cancer and mutation of the EGFR gene in tumor tissue was treated with erlotinib (150 mg daily) and developed an acne-form skin rash 2 weeks later. The rash worsened and laboratory tests showed mild elevations in serum enzymes (ALT 80 U/L with normal AST and serum bilirubin). Because of the rash and stomatitis, erlotinib was stopped. The rash and mouth ulcers resolved rapidly and 2 weeks later erlotinib was restarted; however, 10 days later she developed anorexia and jaundice. She denied fever, chills, rash or abdominal pain. She had no history of liver disease, was not taking other medications, had no risk factors for viral hepatitis and was known to have had normal liver tests in the past (Table). On examination, she was jaundiced and appeared chronically ill. Laboratory tests showed a serum bilirubin of 13.6 mg/dL with marked elevations in serum ALT [2021 U/L] and AST [1476 U/L] and minor elevations in alkaline phosphatase [304 U/L]. Erlotinib was discontinued and she was admitted for management. Liver ultrasound and computerized tomography showed a small amount of ascites, but no evidence of hepatic masses or extrahepatic obstruction. A liver biopsy showed submassive hepatic necrosis with marked portal inflammation and ductular proliferation. Tests for hepatitis A, B and C and Epstein Barr virus infection were negative as were routine autoantibodies. Over the next few days, she experienced worsening jaundice, further prolongation of prothrombin time, hepatic encephalopathy and hepatorenal syndrome, and died on the 11th hospital day. Autopsy was refused.

Key Points

Medication:Erlotinib (100 mg daily)
Pattern:Hepatocellular (R=15)
Severity:5+ (acute liver failure and death)
Latency:11 days after restarting
Recovery:None
Other medications:Budesonide nasal spray and flunisolide inhaler

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
- 3 monthsPre19890.6
0030990.5Erlotinib started
2 weeks0821190.6Skin rash
4 weeks057691.9Erlotinib stopped
Erlotinib restarted 2 weeks after discontinuation, and 1 week after resolution of rash
11 days0202130413.6INR=2.0, Erlotinib stopped
14 days2 days203717418.1Liver biopsy
17 days5 days85713724.1INR=3.4
22 days10 days43714528.4INR=9.0, creatinine 5.0 mg/dL
23 days11 daysPatient died of multiorgan failure
Normal Values <52 <118 <1.2

Comment

Several instances of acute liver failure have been reported in patients treated with erlotinib for non-small cell lung cancer. The onset was abrupt, within days of starting or restarting therapy. The liver disease was rapidly progressive with coagulopathy, hepatic encephalopathy, renal insufficiency and death from multiorgan failure within 1 to 2 weeks of presentation, despite prompt discontinuation of the erlotinib. Liver histology in this case demonstrated a severe acute hepatitis with submassive necrosis. The cause of the injury is unknown, but the rapidity of onset suggests immune factors. Cases of acute hepatitis and acute liver failure were not reported in the preregistration clinical trials of erlotinib that included several thousand patients. Thus, hepatic failure is rare and most likely to occur with rechallenge or if serum enzyme levels are not being monitored.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Erlotinib – Tarceva®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Erlotinib 183321-74-6 C22-H23-N3-O4
Erlotinib Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 28 June 2018

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  • Zenke Y, Umemura S, Sugiyama E, Kirita K, Matsumoto S, Yoh K, Niho S, et al. Successful treatment with afatinib after grade 3 hepatotoxicity induced by both gefitinib and erlotinib in EGFR mutation-positive non-small cell lung cancer. Lung Cancer 2016; 99: 1-3. [PubMed: 27565905]
    (57 year old man with NSCLC developed ALT elevations 7 weeks after starting gefinitib [bilirubin 2.0 mg/dL, ALT peak 594 U/L], which resolved upon stopping but he then developed worsening jaundice within a week of starting erlotinib [bilirubin 5.4 mg/dL, ALT normal], and he later tolerated afatinib; genetic testing revealed Gilbert syndrome and "poor metabolizer" phenotype of CYP 3A5).
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  • Toba H, Sakiyama S, Takizawa H, Tangoku A. Safe and successful treatment with afatinib in three postoperative non-small cell lung cancer patients with recurrences following gefitinib/erlotinib-induced hepatotoxicity. J Med Invest 2016; 63 (1-2): 149-51. [PubMed: 27040072]
    (Two women and one man, ages 63 to 73 years with NSCLC developed ALT elevations 4-8 weeks after starting gefitinib [which recurred in one 6 weeks after switching to erlotinib], but all three tolerated long term afatinib [7 months] without recurrence of enzyme elevations).
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