ArticlesLapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial
Introduction
The human epidermal growth factor receptor 2 (HER2) is a potent mediator of cellular growth and proliferation.1 Amplification of the HER2 gene, and the corresponding overexpression of the HER2 receptor, occurs in roughly 20% of breast tumours and is associated with a poor outcome.2 Molecular targeting of the HER2 receptor with the humanised monoclonal antibody trastuzumab (herceptin, Genentech, San Francisco, CA, USA) has improved disease-free and overall survival in patients with both metastatic and early HER2-positive breast cancer.3, 4, 5 Another anti-HER2 agent, the tyrosine kinase inhibitor lapatinib (tykerb, GlaxoSmithKline, Brentford, UK), given in combination with capecitabine, improves progression-free survival in patients who have progressed on trastuzumab and is approved for treatment of patients with advanced HER2-positive breast cancer.6
Dual targeting of HER2-positive tumours with trastuzumab and lapatinib is undertaken because of primary and acquired resistance to both agents, their partly non-overlapping mechanisms of action, and the well characterised synergistic interaction between them in HER2 breast-cancer models.7, 8, 9 Trastuzumab inhibits ligand-independent HER2 and HER3 signalling10 and triggers antibody-dependent cellular cytotoxicity.11 By contrast, lapatinib blocks ligand-induced heterodimer signalling and prevents signalling via a frequently expressed truncated version of the HER2 receptor that could render cells resistant to trastuzumab. Additionally, lapatinib leads to an accumulation of HER2 at the cell surface, enhancing trastuzumab-dependent antibody-dependent cellular cytotoxicity.9 In a clinic setting, trastuzumab induces mostly a proapoptotic effect, but lapatinib inhibits proliferation.12, 13 Evidence from clinic settings shows indirect evidence in support of dual HER2 blockade. In patients with trastuzumab-refractory breast cancer, lapatinib plus trastuzumab improves progression-free survival when compared with lapatinib alone.14
Preoperative systemic (neoadjuvant) treatment of breast cancer yields disease-free and overall survival results similar to adjuvant systemic therapy of breast cancer and improves breast conservation rates because of tumour response to therapy. The preoperative setting also allows monitoring of response to therapy in previously untreated patients. In HER2-positive breast tumours, pathological complete response (pCR) at time of surgery has been shown to correlate with improved disease outcomes in randomised studies containing trastuzumab and chemotherapy suggesting that it may serve as a surrogate marker of clinical benefit.15, 16
In the NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) study, we assessed lapatinib, trastuzumab, and their combination as neoadjuvant therapy for women with HER2-positive early breast cancer.
Section snippets
Study design and patients
The NeoALTTO trial (Breast International Group 01-06) is a randomised, multicentre, open-label, phase 3 study. From Jan 5, 2008, to May 27, 2010, 455 patients entered the study from 86 sites in 23 countries in Europe, Asia, North and South America, and South Africa. The trial included three parallel treatment groups: oral lapatinib, intravenous trastuzumab, or lapatinib plus trastuzumab given for 6 weeks (the biological window), followed by an additional 12 weeks of the assigned anti-HER2
Results
Figure 1 shows the trial profile. Of 455 patients who were enrolled, 154 women were assigned to the lapatinib group, 149 to the trastuzumab group, and 152 to the group given a combination of lapatinib and trastuzumab (figure 1). The groups were well balanced for hormone-receptor and clinical lymph-node status (table 1). More patients had tumours larger than 5 cm and fewer were candidates for breast-conserving surgery in the trastuzumab group than in the other groups (table 1).
Overall, we
Discussion
Our study provides proof of concept that dual HER2 blockade is better than single agent anti-HER2 therapy, as predicted by findings from laboratory studies.7, 8, 9 The combination of lapatinib and trastuzumab resulted in a significantly higher pCR rate than did trastuzumab or lapatinib alone. The higher pCR rate for the combination was clear across all subgroups tested and was consistent with other studies of anti-HER2 therapies in HER2-positive tumours.23 The pCR rate was higher in patients
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