A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy

O’Shaughnessy, J.; Blackwell, K. L.; Burstein, Harold J.; Storniolo, A. M.; Sledge, G. W.; Baselga, José; Koehler, Maria; Laabs, S.; Florance, Allison; Df, Roychowdhury

doi:10.1200/jco.2008.26.15_suppl.1015

Cited by 137 publications

(86 citation statements)

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“…In first-line patients with trastuzumabnaïve, HER2-positive advanced or MBC, lapatinib monotherapy resulted in 24% ORR . Lapatinib combination therapy has promising efficacy as treatment for HER2-positive advanced or MBC, including treatment-naïve MBC (Geyer et al, 2006;Di Leo et al, 2008;O'Shaughnessy et al, 2008;Johnston et al, 2008a, b). The outcome of this study complements the efficacy reported earlier for lapatinib and confirms that lapatinib offers a beneficial therapeutic option to patients with HER2-overexpressing BC, including those with brain metastases.…”

Section: Discussionsupporting

confidence: 70%

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

et al. 2009

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BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n ¼ 100), objective response rate was 19.0% (95% confidence interval (CI): 11.8 -28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9 -34.7). One out of 22 HER2-negative tumour was documented as complete response (n ¼ 22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P ¼ 0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

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Section: Discussionsupporting

confidence: 70%

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

et al. 2009

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“…A number of studies have confirmed that HER-2 positivity is required for lapatinib clinical benefit [341]. In one recent report, on a clinical trial that originally found limited lapatinib benefit in cases of HER-2-unamplified tumors tested by FISH, lapatinib efficacy was found to be limited to 351 Ross, Slodkowska, Symmans et al…”

Section: Biomarkers Of Lapatinib Resistancementioning

confidence: 99%

“…Data from the ALTTO, Neo-ALTTO, and CHERLOB trials are not yet mature, and efficacy data are currently not available to assess the impact of combining HER-2-targeted agents [336,338,339]. In a recent interim report, testing the efficacy of the combination of trastuzumab and lapatinib compared with lapatinib alone in a heavily pretreated population of HER-2-positive MBC patients who progressed on trastuzumab-based regimens, significant synergy, as measured by the progressionfree survival duration, was shown [351].…”

Section: Trastuzumab-lapatinib Combinations and Other Targeted Therapiesmentioning

confidence: 99%

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

et al. 2009

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1. Contrast the current strengths and limitations of the three main slide-based techniques (IHC, FISH, and CISH) currently in clinical use for testing breast cancer tissues for HER-2 status.2. Compare the efficacy of trastuzumab-and lapatinib-based regimens in the adjuvant and metastatic settings as reported in published clinical trials and regulatory approval databases.3. Contrast the list of biomarkers that have been associated with clinical resistance to trastuzumab and lapatinib and describe their current level of validation.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTThe human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ

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“…In preclinical models, the combination is superior to single drug treatment and enhanced apoptosis has been proposed as a mechanism (Xia et al, 2005;Konecny et al, 2006). In the clinic, a phase III study comparing the efficacy of lapatinib versus the combination of lapatinib and trastuzumab in patients with advanced trastuzumab-resistant HER2-positive breast cancer has shown improved clinical outcome with the combination (O'Shaughnessy et al, 2008). In addition, the combined administration of lapatinib and trastuzumab is being studied in a large adjuvant study.…”

Section: Introductionmentioning

confidence: 99%

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

et al. 2008

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Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially nonoverlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo-(HER2/HER2) and hetero-(HER2/EGFR and HER2/HER3) dimers. Lapatinibinduced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

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A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy

Cited by 137 publications

References 0 publications

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

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