Elsevier

The Lancet

Volume 379, Issue 9816, 18–24 February 2012, Pages 633-640
The Lancet

Articles
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial

https://doi.org/10.1016/S0140-6736(11)61847-3Get rights and content

Summary

Background

The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy.

Methods

In this parallel groups, randomised, open-label, phase 3 study undertaken between Jan 5, 2008, and May 27, 2010, women from 23 countries with HER2-positive primary breast cancer with tumours greater than 2 cm in diameter were randomly assigned to oral lapatinib (1500 mg), intravenous trastuzumab (loading dose 4 mg/m2, subsequent doses 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab. Treatment allocation was by stratified, permuted blocks randomisation, with four stratification factors. Anti-HER2 therapy alone was given for the first 6 weeks; weekly paclitaxel (80 mg/m2) was then added to the regimen for a further 12 weeks, before definitive surgery was undertaken. After surgery, patients received adjuvant chemotherapy followed by the same targeted therapy as in the neoadjuvant phase to 52 weeks. The primary endpoint was the rate of pathological complete response (pCR), analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00553358.

Findings

154 patients received lapatinib, 149 trastuzumab, and 152 the combination. pCR rate was significantly higher in the group given lapatinib and trastuzumab (78 of 152 patients [51·3%; 95% CI 43·1–59·5]) than in the group given trastuzumab alone (44 of 149 patients [29·5%; 22·4–37·5]; difference 21·1%, 9·1–34·2, p=0·0001). We recorded no significant difference in pCR between the lapatinib (38 of 154 patients [24·7%, 18·1–32·3]) and the trastuzumab (difference −4·8%, −17·6 to 8·2, p=0·34) groups. No major cardiac dysfunctions occurred. Frequency of grade 3 diarrhoea was higher with lapatinib (36 patients [23·4%]) and lapatinib plus trastuzumab (32 [21·1%]) than with trastuzumab (three [2·0%]). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (27 [17·5%]) and lapatinib plus trastuzumab (15 [9·9%]) than with trastuzumab (11 [7·4%]).

Interpretation

Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting.

Funding

GlaxoSmithKline.

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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