Blackwell KL, Pegram MD, Tan-Chiu E, Schwartzberg LS, Arbushites MC, Maltzman JD, Forster JK, Rubin SD, Stein SH, Burstein HJSingle-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann Oncol 20: 1026-1031
Department of Medicine/Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA. Annals of Oncology
(Impact Factor: 7.04).
05/2009; 20(6):1026-31. DOI: 10.1093/annonc/mdn759
This phase II study evaluated the efficacy and safety of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer that progressed during prior trastuzumab therapy.
Women with stage IIIB/IV HER2-overexpressing breast cancer were treated with single-agent lapatinib 1250 or 1500 mg once daily after protocol amendment. Tumor response according to RECIST was assessed every 8 weeks. HER2 expression was assessed in tumor tissue by immunohistochemistry and FISH.
Seventy-eight patients were enrolled in the study. Investigator and independent review response rates [complete response (CR) or partial response (PR)] were 7.7% and 5.1%, and clinical benefit rates (CR, PR, or stable disease for >or=24 weeks) were 14.1% and 9.0%, respectively. Median time to progression was 15.3 weeks by independent review, and median overall survival was 79 weeks. The most common treatment-related adverse events were rash (47%), diarrhea (46%), nausea (31%), and fatigue (18%).
Single-agent lapatinib has clinical activity with manageable toxic effects in HER2-overexpressing breast cancer that progressed on trastuzumab-containing therapy. Studies of lapatinib-based combination regimens with chemotherapy and other targeted therapies in metastatic and earlier stages of breast cancer are warranted.
- "The objective response was 6% . This response rate corresponds to that observed in phase II studies evaluating lapatinib in extracerebral metastases in evolution after trastuzumab . Some cohorts have evaluated lapatinib in combination with various chemotherapy regimens in case of BM progression after chemotherapy + trastuzumab and WBI. "
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ABSTRACT: AbstractBreast tumors overexpressing Her2 (15% of breast cancers) are particularly at risk for central nervous system parenchymal metastases. Whole-brain irradiation (WBI) is the standard of care of brain metastases (BM), and secondarily, systemic treatment is used in case of progression. We report the case of a patient with Her2-positive breast tumor with BM developed 10 months after the initial diagnosis of cancer. The BM were initially treated with WBI then trastuzumab before a recurrence occurred, which was controlled during 34 months with lapatinib and capecitabine. The treatment was regularly adjusted according to the tolerance and the efficacy in order to obtain the control of systemic and neurological disease and to maintain the patient's quality of life. Studies on new targeted agents and/or new combinations with chemotherapy are ongoing. This suggests a better efficacy of treatment and an increased survival of patients. However, these patients are sometimes in a very poor general condition. In this case, we show that a good evaluation of efficacy and toxicities may allow an adaptation of the sequence and dose of treatment in order to preserve the response to treatment and the quality of life. Indeed, systemic treatments are available in addition to WBI. Therefore, the objective of the management of BM is twofold: survival and quality of life.
Available from: Teresa Gamucci
- "Lapatinib, an orally available small molecule reversible tyrosine kinase inhibitor and an in vitro and in vivo potent selective dual inhibitor of ErbB1 (EGFR) and HER2 receptor, has been approved since 2007 in combination with capecitabine for treatment of metastatic breast cancer overexpressing HER2 and previously treated with anthracycline , taxane and trastuzumab. Lapatinib inhibits ErbB1 and HER2 intracellular kinase domains; it is known to be active in ErbB1 mutants and truncated forms of HER2 receptor (p95), and can overcome the resistance to trastuzumab (Blackwell et al. 2009; Burstein et al. 2008; Gomez et al. 2008; Iwata et al. 2006). The association of lapatinib and capecitabine was evaluated in a phase III randomized trial (Geyer et al. 2006; Cameron et al. 2010), showing the efficacy of the combination treatment after trastuzumab failure, and the superiority over capecitabine alone in anthracycline and taxane pretreated advanced breast cancer patients. "
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ABSTRACT: Diarrhea in relation to the lapatinib-capecitabine regimen is a common and debilitating side effect which may interfere with optimal treatment delivery. We performed a post hoc analysis in human epidermal growth factor receptor 2-positive advanced breast cancer patients treated with a modified schedule in its administration, aimed primarily to evaluate grade (G) ≥2 diarrhea incidence and, secondarily, treatment efficacy.
Treatment schedule consisted of lapatinib 1,250 mg daily for the first 10 days, then in combination with capecitabine, 2,000 mg/m(2), starting day 11 for the first cycle, and thereafter from day 8, for 14 days of a 21-day cycle, in 3 daily administrations. Lapatinib was dissolved in water, and cholestyramine was continuously given twice a day.
Among 38 patients treated and analyzed, the incidence of G ≥ 2 diarrhea was 13.2 %. In 28 patients diarrhea was not observed, while G1-2 diarrhea was reported in 9 (23.7 %) patients; a single episode of G3 diarrhea was observed in 1 (2.6 %) patient. Overall response rate was 34.2 %, clinical benefit 55.3 %, and median progression-free survival 10 months.
The results of the present post hoc analysis are very encouraging, both in terms of tolerability and treatment efficacy, and all data compare favorably with previous reports of "conventional" administration of the lapatinib-capecitabine regimen.
Available from: PubMed Central
- "Recently, lapatinib (Tykerb, GSK), an ErbB1/2 inhibitor, was approved for the treatment of metastatic breast cancer, as lapatinib is implicated in better outcomes in patients with metastases. Unfortunately, outcomes are still not ideal for patients with metastatic disease [9,10]. Thus therapies which enhance lapatinib-induced cell killing are needed in the clinic. "
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Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. In this study, we examined mechanisms associated with enhancing the activity of lapatinib via combination with other therapies.
In the present studies, estrogen receptor (ER) positive and ER negative breast cancer cells were genetically manipulated to up- or downregulate eIF2-alpha, its phospho-mutant, Nck1, or Nck2, then treated with OSU-03012, lapatinib or the combination and assayed for cytotoxicity/cytostaticity using clonogenic assays.
Treatment of breast cancer cell lines with lapatinib and OSU-03012 (a small molecule derivative of the Cox-2 inhibitor celecoxib) induced synergistic cytotoxic/cytostatic effects. This combination therapy corresponded to an increase in the phosphorylation of eIF2-α at serine51 and a decrease in Nck1 expression. Ectopic expression of phospho-mutant eIF2-α (Ser51Ala) or downregulation of eIF2-α in addition to downregulation of the eIF2-α kinase PERK inhibited the synergistic and cytotoxic effects. Furthermore, ectopic expression of Nck1, but not Nck2 abolished the decrease in cell viability observed in combination-treated cells. Downregulation of Nck1 failed to “rescue” the ablation of the cytotoxic/cytostatic effects by the phospho-mutant of eIF2-α (Ser51Ala) demonstrating that Nck1 downregulation is upstream of eIF2-α phosphorylation in the anti-survival pathway activated by lapatinib and OSU-03012 treatment. Finally, co-immunoprecipitation assays indicated that eIF2-α dissociates from the Nck1/PP1 complex after OSU-03012 and lapatinib co-treatment.
These data indicate that OSU-03012 and lapatinib co-treatment is an effective combination therapy, which functions to enhance cell killing through the Nck1/eIF2 complex. Hence, this complex is a novel target for the treatment of metastatic breast cancer.
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