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DRUG RECORD

 

LAPATINIB

OVERVIEW
Lapatinib

 

Introduction

Lapatinib is a tyrosine kinase receptor inhibitor 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 somewhat since then.  Lapatinib is available in tablets of 250 mg under the brand name Tykerb.  The typical dose of lapatinib is 1,250 mg once daily in combination with capecitabine in cycles of 21 days.  Side effects include rash, diarrhea, nausea, vomiting, fatigue, hand-foot syndrome and pruritus.

 

Hepatotoxicity

Elevations in serum aminotransferase levels are common during lapatinib therapy, occurring in 5% to 15% of patients.  Values greater than 5 times the upper limit of normal (ULN) occur in a smaller percentage.  These abnormalities are usually 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.

 

Mechanism of Injury

The clinical features of cases of acute liver injury from the tyrosine kinase receptor inhibitors suggest that they are 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.

 

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

 

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CASE REPORT
Lapatinib

 

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 Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
Pre Pre 24 120 0.8  
10 days Pre 30 110 0.7 Capecitabine stopped
4 weeks 0 583 348 4.1 Lapatinib stopped
6 weeks 2 weeks 481 310 11.8 Liver biopsy
2 months 1 month 260 318 2.7
3 months 2 months 229 298 2.3
4 months 3 months 44 246 0.9
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.

 

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PRODUCT INFORMATION
Lapatinib

 

REPRESENTATIVE TRADE NAMES
Lapatinib – Tykerb®

 

DRUG CLASS
Antineoplastic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Lapatinib 231277-92-2 C29-H26-Cl-F-N4-O4-S Lapatinib Chemical Structure

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References updated: 20 February 2014

  1. 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).

  2. DeLeve LD. Kinase inhibitors. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556-7.  (Review of hepatotoxicity of cancer chemotherapeutic agents; discusses gefitiinib, erlotinib and crizotinib but not imatinib or lapatinib).

  3. Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Protein tyrosine kinase inhibitors. 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. 1731-8.  (Textbook of pharmacology and therapeutics).

  4. Medina PJ, Goodin S. Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther 2008; 30: 1426-47. PubMed Citation  (Review of chemistry, pharmacology, mechanism of action, clinically efficacy and toxicity of lapatinib, a dual inhibitor of EGFR and HER2, approved for use in patients with advanced breast cancer typically used in combination with capecitabine; common side effects are diarrhea, hand-foot syndrome, nausea, rash and fatigue; no mention of ALT elevations or clinically apparent liver injury).

  5. Ryan Q, Ibrahim A, Cohen MH, Johnson J, Ko CW, Sridhara R, Justice R, et al. FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist 2008; 13: 1114-9. PubMed Citation  (Summary of FDA analyses of trials of lapatinib in breast cancer providing the basis for its approval; ALT elevations occurred in 37% of patients given lapatinib and capecitabine and in a similar proportion given capecitabine alone; clinically apparent liver injury was not mentioned).

  6. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355: 2733-43. PubMed Citation  (In a phase III trial in 324 women with breast cancer, the combination of lapatinib and capecitabine in comparison to capecitabine alone increased progression free survival from 4.1-8.4 months; lapatinib therapy was associated with higher rates of diarrhea, rash and dyspepsia; ALT elevations and clinically apparent liver injury were not mentioned).

  7. Bekaii-Saab T, Markowitz J, Prescott N, Sadee W, Heerema N, Wei L, Dai Z, et al. A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res 2009; 15: 5895-901. PubMed Citation  (Among 26 patients with hepatocellular carcinoma treated with lapatinib, ALT elevations occurred in 5 [19%], but none were above 5 times ULN and none required dose discontinuation or were associated with clinically apparent liver injury).

  8. Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz HJ, Yen Y, Kindler HL, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009; 64: 777-83. PubMed Citation  (Among 57 patients with unresectable hepatobiliary carcinomas treated with one to twelve 28 day cycles of lapatinib, almost half required dose modification and 9% developed ALT elevations >5 times ULN, but none developed clinically apparent liver injury).

  9. Tevaarwerk AJ, Kolesar JM. Lapatinib: a small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor-2 tyrosine kinases used in the treatment of breast cancer. Clin Ther 2009; 31 Pt 2: 2332-48. PubMed Citation  (Review of the mechanism of action, pharmacology, efficacy and safety of lapatinib; no discussion of hepatotoxicity).

  10. Macfarlane RJ, Gelmon KA. Lapatinib for breast cancer: a review of the current literature. Expert Opin Drug Saf 2011; 10: 109-21. PubMed Citation  (Systematic review of the literature on the efficacy and safety of lapatinib in therapy of breast cancer; hepatotoxicity is not discussed).

  11. 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  (60 year old woman with breast cancer developed jaundice 2 weeks after starting lapatinib [bilirubin 4.1 mg/dL, ALT 583 U/L, Alk P 348 U/L], biopsy showing bridging necrosis and eosinophils, resolving within 3 months of stopping).

  12. Spraggs CF, Budde LR, Briley LP, Bing N, Cox CJ, King KS, Whittaker JC, Mooser VE, Preston AJ, Stein SH, Cardon LR. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol 2011; 29: 667-73. PubMed Citation  (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).

  13. Spraggs CF, Parham LR, Hunt CM, Dollery CT. Lapatinib-induced liver injury characterized by class II HLA and Gilbert's syndrome genotypes. Clin Pharmacol Ther 2012; 91: 647-52. PubMed Citation  (Genetic analyses on 20 cases of suspected lapatinib hepatotoxicity with jaundice found that 8 had Gilbert syndrome and 14 had HLA-DQA1*02.01 and DRB1*07.01; the absence of the HLA alleles was highly predictive for absence of hepatotoxicity, but its positive predictive value was low).

  14. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Det al; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012; 379 (9816): 633-40. PubMed Citation  (Among 455 women with HER2-positive breast cancer treated with lapatinib or trastuzumab or both, response rates were similar between the individual agents, but was greater with the combination; hepatic adverse events occurred in 27 [17.5%] lapatinib, 11 [7.4%] trastuzumab, and 15 [9.9%] combination treated women).

  15. Castellino S, O'Mara M, Koch K, Borts DJ, Bowers GD, MacLauchlin C. Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity. Drug Metab Dispos 2012; 40: 139-50. PubMed Citation  (Pharmacokinetic studies in 6 healthy adults showed high intersubject variability, and several of the many intermediates detected were potential reactive metabolites).

  16. Kaniwa N, Saito Y. Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury. J Hum Genet 2013; 58: 317-26. PubMed Citation  (Review of genetic studies of severe cutaneous and hepatic adverse events; HLA DQA1*02.01 has been associated with lapatinib hepatotoxicity, mainly in Europeans [Spraggs 2011]).

  17. Shah RR, Morganroth J, Shah DR. Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives. Drug Saf 2013; 36: 491-503. PubMed Citation  (Thorough review of the hepatotoxicity of 16 tyrosine kinase inhibitors including lapatinib which is associated with ALT elevations in 37-53% of subjects [2-6% above 5 times the ULN] and cases of clinically apparent and fatal liver injury).

  18. Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics 2013; 14: 541-54. PubMed Citation  (Review of the use of genetic testing in use of tyrosine kinase inhibitors lapatinib and pazopanib).

  19. Karczmarek-Borowska B, Sałek-Zań A. Hepatotoxicity of molecular targeted therapy. Contemp Oncol (Pozn) 2015; 19: 87-92. PubMed Citation  (Review of hepatotoxicity of modern molecular targeted therapies including monoclonal antibodies, protein kinase inhibitors and proteosome inhibitors; lapatinib has an increased risk of liver injury).

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OTHER REFERENCE LINKS
Lapatinib

  1. PubMed logoRecent References on Lapatinib

  2. Clinical Trials logoTrials on Lapatinib

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