Phase I and Pharmacokinetic Study of Lapatinib in Combination With Capecitabine in Patients With Advanced Solid Malignancies

Chu, Quincy S.; Schwartz, Garry; Bono, Johann S. de; Smith, Deborah A.; Koch, Kevin M.; Versola, M.; Pandite, Lini; Arya, Nikita; Curtright, J.; Fleming, Ronald A.; Ho, Peter; Rowinsky, Eric K.

doi:10.1200/jco.2007.11.1765

Cited by 58 publications

(42 citation statements)

References 17 publications

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“…A phase I pharmacokinetic study has shown that peak plasma concentration of lapatinib is 2.43 mg/mL (¼ 2.58 mmol/L; ref. 29). Consistently, lapatinib alone could not affect the viability of HER2-positive SCLC cells up to this concentration ( Supplementary Fig.…”

Section: Lapatinib Restores Chemosensitivity In Abc Transporter-positsupporting

confidence: 49%

HER2 As Therapeutic Target for Overcoming ATP-Binding Cassette Transporter–Mediated Chemoresistance in Small Cell Lung Cancer

Minami

Kijima

Otani

et al. 2012

Molecular Cancer Therapeutics

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Small cell lung cancer (SCLC) easily acquires multidrug resistance after successful initial therapy. Overexpression of ATP-binding cassette (ABC) transporters is important for the multidrug resistance. Among them, ABCB1 and ABCG2 are known to be upregulated in chemoresistant SCLC cells. We found that human epidermal growth factor receptor 2 (HER2) expressions are also upregulated in chemoresistant SBC-3/ETP, SBC-3/SN-38, and SBC-3/CDDP cells, compared with chemosensitive SBC-3 cells. Lapatinib, a tyrosine kinase inhibitor of HER2, could not suppress proliferation of these HER2-positive SCLC cells alone but successfully restored chemosensitivity to etoposide and SN-38 with a clinically applicable concentration. The reversal effect of lapatinib was thought to be caused by inhibition of drug efflux pump functions of ABC transporters, although lapatinib itself has been reported to be a substrate for them. Moreover, knocking down of HER2 by an short interfering RNA weakened the effect of lapatinib on ABCB1, indicating the involvement of HER2 in the inhibitory mechanisms. Notably, we showed that caveolin-1 and Src play key roles in modulating ABCB1 function via HER2 inactivation. In SBC-3/ETP cells, dephosphorylation of HER2 by lapatinib activates Src and successively leads to increased caveolin-1 phosphorylation. Through this process, caveolin-1 dissociates from HER2 and strengthens association with ABCB1, and finally impairs the pump functions. Furthermore, we showed that treatment by lapatinib in combination with etoposide or irinotecan significantly suppresses the growth of subcutaneous SBC-3/ETP and SBC-3/SN-38 tumors in mice, respectively. Collectively, these results indicate that combination therapy with lapatinib and cytotoxic agents could conquer ABC transportermediated chemoresistance especially in HER2-positive SCLC. Mol Cancer Ther; 11(4); 830-41. Ó2012 AACR.

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Section: Lapatinib Restores Chemosensitivity In Abc Transporter-positsupporting

confidence: 49%

HER2 As Therapeutic Target for Overcoming ATP-Binding Cassette Transporter–Mediated Chemoresistance in Small Cell Lung Cancer

Minami

Kijima

Otani

et al. 2012

Molecular Cancer Therapeutics

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“…Phase I clinical studies have proven the safety of lapatinib administration either alone 35,36 or in combination with another oral agent, capecitabine 37,38 . In the phase I study of Burris et al 36 , out of 67 patients with advanced solid tumors displaying HER1 expression by immunohistochemistry (IHC) and/or HER2 overexpression by IHC or amplification by fluorescence in situ hybridization (FISH) 30 (44.7%) were treated for BC.…”

Section: Clinical Studiesmentioning

confidence: 99%

“…In the phase I study of Burris et al 36 , out of 67 patients with advanced solid tumors displaying HER1 expression by immunohistochemistry (IHC) and/or HER2 overexpression by IHC or amplification by fluorescence in situ hybridization (FISH) 30 (44.7%) were treated for BC. Patients who experienced complete remission, partial response (PR) or stable disease in the phase I studies were mainly those suffering from BC 36,38 . The phase II study in HER2+ MBC patients after trastuzumab treatment failure, produced more results supporting the safety of lapatinib and it evaluated its benefits 39,40 .…”

Section: Clinical Studiesmentioning

confidence: 99%

Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

Bouchalová¹,

Cizkova²,

Cwiertka³

et al. 2010

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Breast cancer treatment trends are currently based on tailored therapies using tumor and patient biomarkers. Lapatinib is the first dual inhibitor of HER1 (EGFR, ErbB1) and HER2 (ErbB2, Neu) tyrosine kinases to be used in clinical practice. However, only HER2 is currently used for therapy indications and new predictors for the treatment with lapatinib are sought.Methods and results. This minireview focuses on lapatinib and its role in breast cancer treatment. Preclinical and clinical studies as well as pharmacological characteristics are briefly reviewed while the focus is on efficacy assessment including predictive factors for therapy outcome.Conclusion. Lapatinib (Tykerb/Tyverb) was Food and Drug Administration (FDA) approved in 2007 for use in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in patients who had received previous treatment (including anthracycline, taxane and trastuzumab containing regimens) and in 2010 for use in combination with letrozole for postmenopausal women with hormonal receptor positive and HER2-positive metastatic breast cancer. In contrast to trastuzumab (Herceptin), lapatinib is orally administered and it targets both HER2 and HER1 receptors. As a synthetic and oral tyrosine kinase inhibitor (TKI), it is convenient, cheaper and easier to produce than monoclonal antibodies. The recommended dosage is not dependent on body weight either. Lapatinib plasma level measurement could be an approach to tailored therapy for further optimizing the dose and prolonging this efficient therapy. New lapatinib response predictors are being evaluated. At this time, only HER2

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“…A phase I study (EGF10005) found the optimal tolerated regimen for the combination to be 1250 mg lapatinib daily and 2000 mg/m 2 /day capecitabine on days 1 to 14 of a 21-day cycle. Four confi rmed responses from 45 patients were reported, including 2 breast malignancies (1 complete response and 1 partial response) (Chu et al 2007). The complete response occurred in a patient that had disease progression while receiving trastuzumab.…”

Section: Lapatinib In Combination With Chemotherapymentioning

confidence: 99%

“…The AUC for SN-38 increased by 41% and C max increased by 32%. No significant pharmacokinetic interactions have been found between lapatinib and capecitabine (Chu et al 2007), trastuzumab , letrozole (GlaxoSmithKline), oxaliplatin and 5-FU (Siegel-Lakhai et al 2007), or docetaxel (GlaxoSmithKline).…”

Section: Potential Drug Interactionsmentioning

confidence: 99%

Targeted treatment of advanced and metastatic breast cancer with lapatinib

Corkery

O’Donovan²,

Crown³

2008

OTT

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Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER-2 and EGFR. Lapatinib is a potent dual inhibitor of HER-2 and EGFR. Preclinical and phase I studies have shown activity with lapatinib in a number of cancers, including breast cancer, and the drug is well tolerated. The main known drug interactions are with paclitaxel and irinotecan. The most signifi cant side-effects of lapatinib are diarrhea and adverse skin events. Rates of cardiotoxicity compare favorably with trastuzumab, a monoclonal antibody against HER-2. This paper focuses on lapatinib in advanced and metastatic breast cancer, which remains an important therapeutic challenge. Phase II and III studies show activity as monotherapy, and in combination with chemotherapy or hormonal agents. Results from these studies suggest that the main benefi t from lapatinib is in the HER-2 positive breast cancer population. Combinations of lapatinib and trastuzumab are also being studied and show encouraging results, particularly in trastuzumab-refractory metastatic breast cancer. Lapatinib may have a specifi c role in treating HER-2 positive CNS metastases. The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated.

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Phase I and Pharmacokinetic Study of Lapatinib in Combination With Capecitabine in Patients With Advanced Solid Malignancies

Abstract: Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.

Cited by 58 publications

References 17 publications

HER2 As Therapeutic Target for Overcoming ATP-Binding Cassette Transporter–Mediated Chemoresistance in Small Cell Lung Cancer

HER2 As Therapeutic Target for Overcoming ATP-Binding Cassette Transporter–Mediated Chemoresistance in Small Cell Lung Cancer

Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

Targeted treatment of advanced and metastatic breast cancer with lapatinib

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