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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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Lapatinib

Last Update: May 15, 2019.

OVERVIEW

Introduction

Lapatinib is a small molecule inhibitor of several tyrosine kinase receptors involved in tumor cell growth that is used in the therapy of advanced breast cancer and other solid tumors. Lapatinib therapy is associated with transient elevations in serum aminotransferase levels and rare instances of clinically apparent acute liver injury.

Background

Lapatinib (la pa' ti nib) is a selective inhibitor of two tyrosine kinase receptors which are associated with tumor growth and angiogenesis. Lapatinib has special activity against the epidermal growth factor receptor (EGFR) and the human epidermal group factor receptor-2 (HER2). Tyrosine kinase receptors are often mutated and over expressed in cancer cells, causing unregulated cell growth and proliferation. Lapatinib 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 these receptors can lead to dramatic reversal of progression the cancer, although the efficacy is sometimes limited by the development of tumor resistance caused by mutations in the kinase. Lapatinib received approval for use in the United States in 2007 for treatment of patients with advanced or metastatic breast cancer whose tumors over express HER2 to be used in combination with capecitabine. Indications have been broadened since then to include its combination with letrozole in women with advanced breast cancer in whom hormonal therapy is indicated. Lapatinib is available in tablets of 250 mg generically and under the brand name Tykerb. The typical dose of lapatinib in combination with capecitabine is 1,250 once daily in cycles of 21 days and when combined wtih letrozole is 1,500 mg given once daily continuously. Side effects include rash, diarrhea, nausea, vomiting, fatigue, hand-foot syndrome and pruritus. Rare, but potentially severe adverse events include interstitial lung disease, cardiovascular complications, hypersensitivity reactions and embryo fetal toxicity.

Hepatotoxicity

Elevations in serum aminotransferase levels are common during lapatinib therapy, occurring in up to half of patients. Values greater than 5 times the upper limit of normal (ULN) occur in 2% to 6% of patients but are usually transient and asymptomatic. Dose adjustments or temporary discontinuations are rarely required for liver test abnormalities.

Since its introduction into clinical use, lapatinib has been linked to several cases of clinically apparent acute liver injury. The clinical features of injury have not been well defined, but the onset is usually within 1 to 3 months of starting lapatinib and the pattern of serum enzyme elevations is typically hepatocellular or mixed (Case 1). Sufficent numbers of reports of liver injury have been made to the Food and Drug Administration such that lapatinib is listed as having hepatotoxicity that can be fatal. The frequency of serious liver injury is estimated to be 0.2%, but is likely higher. Immunoallergic and autoimmune features are uncommon, although genetic studies suggest that lapatinib hepatotoxicity is linked to specific HLA alleles. Most instances are self-limited, but several cases of acute liver failure have been reported with tyrosine kinase receptor inhibitors including imatinib, sunitinib, lapatinib, gefitinib and erlotinib. Recurrence of injury is common with reexposure but may not occur upon switching to another kinase receptor inhibitor.

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

Mechanism of Injury

The clinical and genetic findings associated with acute liver injury from the tyrosine kinase receptor inhibitors suggest that it is immune mediated. Lapatinib is metabolized in the liver largely through the CYP 3A4 and CYP 3A5 pathways, and liver injury may be due to production of a toxic or immunogenic intermediate. Genetic analyses have shown a close correlation of lapatinib liver injury with the HLA alleles DQA1*02:01 and DRB1*07:01. In large retrospective analyses of trials of lapatinib in early stage breast cancer, ALT elevations above 5 times ULN occurred in 7.7% of DRB1*07:01 carriers versus 0.5% of controls.

Outcome and Management

Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation. There does not appear to be cross reactivity of the hepatic injury among the tyrosine kinase receptor inhibitors and, in some situations, switching to another inhibitor may be appropriate. In using lapatinib, other potentially hepatotoxic agents should be avoided.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

CASE REPORT

Case 1. Acute hepatitis due to lapatinib.

[Modified from: Peroukides S, Makatsoris T, Koutras A, Tsamandas A, Onyenadum A, Labropoulou-Karatza C, Kalofonos H. Lapatinib-induced hepatitis: a case report. World J Gastroenterol 2011; 17: 2349-52. PubMed Citation]

A 60 year old woman with metastatic, HER2-positive breast cancer was treated with lumpectomy and axillary lymph node dissection followed by local irradiation, several cycles of adjuvant chemotherapy, long term exemestane and a one year course of trastuzumab. She was free of evidence of disease for three years, but then was found to have 3 suspicious nodules on computerized tomography (CT) of the chest. Exemestane was discontinued and she was started on chemotherapy with capecitabine (1000 mg/m2 twice daily) and lapatinib (1250 mg daily). Capecitabine was stopped after 10 days because of diarrhea, and she was maintained on lapatinib alone. Two weeks later and four weeks after starting lapatinib, she developed jaundice with few other symptoms. Physical examination showed hepatomegaly without rash or fever. She denied taking other medications, a previous history of liver disease or jaundice, risk factors for viral hepatitis or excessive alcohol use. Laboratory tests showed a total bilirubin of 4.1 mg/dL, ALT 583 U/L, AST 457 U/L, alkaline phosphatase 348 U/L, GGTP 213 U/L and INR 1.14 (Table). Lapatinib was stopped. Tests for hepatitis A, B and C were negative as were autoantibodies. Abdominal ultrasound and CT scan showed no evidence of biliary obstruction or hepatic masses. Jaundice deepened for the first 2 weeks after stopping lapatinib. A liver biopsy showed bridging hepatic necrosis and portal inflammation with eosinophils. Thereafter, she began to improve and all liver tests were normal in follow up 3 months later.

Key Points

Medication:Lapatinib (1250 mg daily)
Pattern:Hepatocellular (R=10)
Severity:3+ (jaundice, hospitalization)
Latency:4 weeks
Recovery:3 months
Other medications:Previously, capecitabine, exemestane.

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
PrePre241200.8
10 daysPre301100.7Capecitabine stopped
4 weeks05833484.1Lapatinib stopped
6 weeks2 weeks48131011.8Liver biopsy
2 months1 month2603182.7
3 months2 months2292982.3
4 months3 months442460.9
Normal Values<45<270<1.2

Comment

A moderately severe acute hepatitis occurred a month after starting lapatinib in a woman with metastatic breast cancer. She was not taking other medications and other causes of liver injury were adequately excluded. Despite stopping lapatinib at the onset of jaundice, she continued to worsen for several weeks, which prompted a liver biopsy that was interpreted as consistent with drug induced liver injury. Recovery was somewhat slow, but complete by 3 months after onset. At the time of this report, there had been no published cases of lapatinib hepatotoxicity. HLA testing was not reported, but subsequent studies have identified the HLA allele DQA1*02:01 as a major risk factor for lapatinib associated hepatotoxicity, the same allele that was linked to ximelagatran related liver injury.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Lapatinib – Tykerb®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Lapatinib231277-92-2C29-H26-Cl-F-N4-O4-S
Lapatinib Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 15 May 2019

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    (Genetic analyses in 37 women with breast cancer treated with lapatinib who developed serum ALT elevations during treatment and 286 controls, followed by confirmatory testing of 24 cases and 155 controls identified the HLA allele DQA1*02:01 as present in 71% of cases vs 21% of controls).
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 were attributed to antineoplastic agents [5.5%], 9 of which were due to kinase inhibitors [6 icteric, none fatal] including 5 from imatinib, 2 lapatinib, 1 regorafenib and 1 cediranib).
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    (Genome wide evaluation of 34 cases of suspected lapatinib hepatotoxicity and 810 controls failed to find any significant association outside of the previously identified HLA-DRB1*07:01 associated polymorphisms and no additional associated individual variants were identified by whole genome sequencing of 26 cases and 19 controls).
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    (Among 8381 women with HER2 positive early breast cancer given adjuvant therapy for one year, addition of lapatinib did not improve disease free survival compared to trastuzumab alone and total, serious and dose-modifying adverse events were more frequent with its use including "hepatobiliary" adverse events 3-4% vs 1%, 3 of which were fatal [details not provided]).
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    (Among 142 women with metastatic HER2 positive breast cancer treated with lapatinib combined with either capecitabine, vinorelbine or gemcitabine, overall response rates and progression-free survival were similar in the three groups and ALT elevations occured in 12-40% of patients, which were above 5 times ULN in 4-13%, the highest rates being in those receiving gemcitabine).
  • Faulkner L, Meng X, Naisbitt DJ, Spraggs CF, Park BK. No evidence for drug-specific activation of circulating T cells from patients with HLA-DRB1*07:01-restricted lapatinib-induced liver injury. Chem Res Toxicol 2016; 29: 2111-3. [PubMed: 27989141]
    (T cells from lapatinib treated patients with and without a history of liver injury during treatment showed no consistent response to in vitro exposure to lapatinib and T cell cloning identified no drug-specific clones).
  • Romero Carreño E, Marcos Rodríguez JA, Santana Martínez S, de la Cruz Merino L. [Hepatic toxicity in HER-2(+) breast cancer patient under treatment with capecitabine and lapatinib]. Farm Hosp 2016; 40: 134-6. [PubMed: 26980172]
    (31 year old woman with metastatic HER2 positive breast cancer developed liver tests abnormalities while on lapatinib and capecitabine and valproate and levetiracetam for brain metastases [ALT 134 U/L, Alk P 755 U/L, bilirubin 2.3 mg/dL], which improved after stopping valproate and lapatinib, although she was later able to tolerate lapatinib at a lower dose).
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    (Review of the hepatotoxicity of recently approved medications including the tyrosine kinase inhibitors and lapatinib).
  • Petros Z, Makonnen E, Aklillu E. Genome-wide association studies for idiosyncratic drug-induced hepatotoxicity: looking back-looking forward to next-generation innovation. OMICS 2017; 21: 123-31. [PMC free article: PMC5346905] [PubMed: 28253087]
    (Review of genome-wide association studies for idiosyncratic liver injury mentions that lapatinib has been associated with DRB1*07:01 in several large studies).
  • Miners JO, Chau N, Rowland A, Burns K, McKinnon RA, Mackenzie PI, Tucker GT, et al. Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: implications for hyperbilirubinemia. Biochem Pharmacol 2017; 129: 85-95. [PubMed: 28065859]
    (Lapatinib, pazopanib, regorafenib and sorafenb were assessed in vitro for inhibition of UDP-glucuronosyltransferase enzymes and all were found to inhibit UGT1A1-catalyzed bilirubin glucuronidation, perhaps explaining hyperbilirubinemia during therapy with these tyrosine kinase inhibitors).
  • Spraggs CF, Parham LR, Briley LP, Warren L, Williams LS, Fraser DJ, Jiang Z, et al. Characterisation of the HLA-DRB1*07:01 biomarker for lapatinib-induced liver toxicity during treatment of early-stage breast cancer patients with lapatinib in combination with trastuzumab and/or taxanes. Pharmacogenomics J 2018; 18: 480-6. [PubMed: 28786423]
    (Among 8381 patients with metastatic breast cancer treated with lapatinib or trastuzumab or their combination, ALT elevations above 5 times ULN were more frequent in lapatinib treated subjects and rates were higher in HLA-DRB1*07:01 carriers [homozygous 8.6% and heterozygous 12.9%] vs non-carriers [1.5%], and no such association was found in subjects with elevations treated with trastuzumab alone).

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