Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer
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Lapatinib
Trastuzumab emtansine
Pertuzumab
Antibody-drug conjugate
Humanized antibody
Abstract Trastuzumab emtansine (T‐DM1) is an antibody‐drug conjugate in development for human epidermal growth factor receptor 2 (HER2)‐positive cancer. Drugs in development are generally tested for their effects on QT interval, prolongation of which is associated with the potentially fatal arrhythmia torsades de pointes. In addition, an association between left ventricular dysfunction and other HER2‐directed agents has been documented. This multicenter, phase 2 study, TDM4688g, assessed the safety and pharmacokinetic characteristics of T‐DM1 (3.6 mg/kg every 3 weeks) in patients with previously treated HER2‐positive metastatic breast cancer, and the safety of pertuzumab plus T‐DM1, an anti‐HER2 extracellular domain antibody, in patients with early disease progression on T‐DM1 alone. The primary end point was the change in QTc interval from baseline to each postbaseline time point, adjusted for heart rate using Fridericia's correction. T‐DM1 had no clinically relevant effect on QTc interval. The observed upper limit of the one‐sided 95% confidence interval was below the 10‐millisecond threshold of safety concern. The safety and efficacy of single‐agent T‐DM1 was consistent with that observed in previous studies. Pertuzumab plus T‐DM1 was generally well tolerated with no new safety signals. These results support further investigation of T‐DM1 as a single agent and with pertuzumab.
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Trastuzumab emtansine
Lapatinib
Torsades de pointes
Clinical endpoint
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HER2 overexpression occurs in about 15-20% of breast cancer cases and is associated with rapid tumor growth. The introduction in clinical practice of several drugs inhibiting the biological activity of HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and lapatinib, has clearly modified the prognosis for these patients. The combination of the two inhibitors of HER2, trastuzumab and pertuzumab, with a taxane (paclitaxel or docetaxel), is currently considered the first choice treatment for patients affected by HER2-positive metastatic breast cancer, whereas T-DM1 is considered the preferred treatment after the failure of first line therapy. We present the case of a 50-year-old woman affected by HER2-positive breast cancer with bone, hepatic, pulmonary and encephalic metastases, resistant both to trastuzumab-pertuzumab double-block treatment and to T-DM1, but sensitive to third line therapy to the combination lapatinib-capecitabine with a clinical response both for visceral and cerebral metastases (Oncology).
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The overexpression of the HER2 receptor and its gene amplification are observed in c. 20% of newly diagnosed cases of breast cancer and associated with a more aggressive clinical course and poorer prognosis. New HER2-targeted drugs, such as lapatinib, pertuzumab and trastuzumab emtansine, significantly improve patient outcomes. The article reviews the role of lapatinib in HER-targeted therapy and describes the treatment sequence of two women with HER2-positive advanced breast cancer.
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Human epidermal growth factor receptor 2 (HER2)-targeted therapies have revolutionized the treatment of HER2-positive breast cancer, both in the metastatic and early stage settings. While trastuzumab and lapatinib had been the mainstays of treatment in combination with chemotherapy, innate and acquired resistance to these therapies occur. More recently, two additional HER2-directed therapies have been approved for HER2-positive breast cancer. Pertuzumab is a humanized monoclonal antibody that binds to the extracellular portion of the receptor on a domain distinct from the binding site of trastuzumab. The addition of pertuzumab to trastuzumab results in synergistic tumor cell inhibition and has been shown to significantly improve clinical outcomes for patients with HER2-positive metastatic breast cancer (MBC) compared to trastuzumab plus chemotherapy alone. In addition, ado-trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate linking trastuzumab with the cytotoxic maytansinoid, DM1, is an effective treatment for HER2-positive breast cancer that has progressed on other HER2-directed therapies. Both pertuzumab and T-DM1 are relatively well tolerated. This review presents the mechanisms of action as well as phase I, II and III clinical data describing the safety and efficacy of pertuzumab and T-DM1 for HER2-positive breast cancer.
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Humanized antibody
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The human epidermal growth factor receptor HER2/neu gene is amplified and overexpressed in 25 to 30% of breast cancers. In women with HER2-positive advanced or metastatic breast cancer, the anti-HER2 monoclonal antibody trastuzumab and the dual tyrosine kinase inhibitor lapatinib are both established options used in combination with cytotoxic chemotherapy. In patients who progress after first-line therapy with trastuzumab plus chemotherapy, continued trastuzumab or switching to lapatinib, both in combination with cytotoxic chemotherapy, offers clinical benefit. New agents in the metastatic disease setting include pertuzumab and trastuzumab emtansine. In the first-line setting, the addition of pertuzumab to trastuzumab/docetaxel yields longer median progression-free survival than placebo plus trastuzumab/docetaxel (18.5 vs. 12.4 months; p < 0.001). In the second-line setting, trastuzumab emtansine alone improves median progression-free survival compared with capecitabine plus lapatinib (9.6 vs. 6.4 months; p < 0.0001). The combination of trastuzumab emtansine plus pertuzumab has also shown encouraging preliminary activity. Other agents in clinical development include subcutaneous trastuzumab, afatinib, and neratinib. Numerous other treatments across a range of drug classes are currently in development for the treatment of HER2-positive metastatic breast cancer.
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Metastatic breast cancer (MBC) overexpressing human epidermal growth factor receptor-2 (HER2) once had an overall worse prognosis, but therapies targeting HER2 have altered the natural course of HER2-positive disease. The initial success of trastuzumab in improving survival rates led to the clinical development of lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). HER2 protein overexpression and/or gene amplification remain the most important predictive factors for response to HER2-targeted therapies. The optimal duration of chemotherapy (CT) is at least 4–6 months (or longer) and/or to the time of maximal response, depending on toxicity and the absence of progression. HER2-targeted therapy continues until progression or unacceptable toxicity. For patients with estrogen receptor–positive/progesterone receptor–positive breast cancer who are not good candidates for CT or wish to avoid the toxicity of CT, initial hormone therapy in combination with HER2-targeted therapy is a reasonable option. For patients who relapse and were previously treated with adjuvant anti-HER2 therapy, the resumption of systemic treatment that includes HER2 blockade is recommended. As in the first-line setting, multiple choices are available for second- and third-line therapies. Successful targeting of HER2 has improved outcomes in HER2-positive breast cancer, but treatment resistance and brain metastases remain a problem. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in HER2-positive tumors.
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Lapatinib is an intracellular tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2) receptors, approved for the treatment of metastatic breast carcinoma pre-treated with anti-HER2 antibodies. We report the case of a 60-year-old woman diagnosed with metastatic breast neoplasm, HER2-positive, progressing after treatment with trastuzumab, pertuzumab and T-DM1, who obtained a regression of hepatic metastases after treatment with lapatinib-capecitabine (Oncology).
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Human epidermal growth factor receptor-2 (HER2/ErbB-2) is a receptor tyrosine kinase involved in cell growth and differentiation and over-expressed in about 15-30% of breast cancers. Trastuzumab is an anti-HER2 monoclonal antibody that has significantly improved survival of patients with early and metastatic breast cancer (BC). However, 65% patients experience primary and secondary resistance. This article explores existing and emerging combination therapy for HER2 positive breast cancer, highlighting the success of trastuzumab in combination with another monoclonal antibody, pertuzumab and small molecule tyrosine kinase inhibitors lapatinib and neratinib. Recent studies have indicated that combination of trastuzumab, pertuzumab and lapatinib increases the 3-year overall survival from 90% to 95% in metastatic BC patients. The EPHOS-B trial has shown a remarkable shrinkage of the tumour when lapatinib is used before surgery and chemotherapy. Despite this success, pertuzumab has just been approved for use in the British National Health Service (NHS) while pertuzuamb, lapatinib and neratinib have been approved for European and American markets for a number of years. Lapatinib and neratinib are not available yet in UK. Strict assessment criteria on cost-benefits might limit the access to these drugs to British cancer patients.
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Abstract Breast cancer (BC) is the second most common cancer and the second leading cause of mortality among women globally. Approximately 20 to 25% of BC patients have amplification of the human epidermal growth factor receptor 2 (HER2) genes, a marker of poor prognosis. However, the introduction of anti-HER2-therapies (trastuzumab, followed closely by lapatinib, pertuzumab, trastuzumab emtansine, and neratinib) has changed the natural history of HER2-positive BC and improved the outcome in HER2-positive BC patients. The preeminence of anti-HER2 combination therapy in achieving complete inhibition of the various HER receptor dimers has been demonstrated in clinical studies. However, despite these therapeutic advances, tumors expressing estrogen receptor have poorer responses to targeted therapy and are more likely to relapse. A better understanding of resistance to existing anti-HER2 agents, along with the role played by the microenvironment and of interconnected signaling pathways, can permit tailor-made therapeutic options for each patient. This review aimed to evaluate treatment approaches for BC patients with HER2-positive disease in the adjuvant and neoadjuvant settings, also exploring the possibilities of extended duration of anti-HER2 maintenance therapy.
Lapatinib
Pertuzumab
Neratinib
Trastuzumab emtansine
Targeted Therapy
Adjuvant Therapy
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The combination of the antibody-drug conjugate ado-trastuzumab emtansine, or T-DM1, plus pertuzumab given prior to surgery outperformed standard therapy in women with HER2-positive breast cancer enrolled in the I-SPY 2 trial. The results, reported at the American Association for Cancer Research Annual Meeting 2016, suggest that the drug combination would be successful in a phase III trial, potentially leading to an effective, less toxic treatment option for women at risk for metastatic disease.
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Antibody-drug conjugate
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