[S3-3] First Results of the NeoALTTO Trial (BIG 01-06 / EGF 106903): A Phase III, Randomized, Open Label, Neoadjuvant Study of Lapatinib, Trastuzumab, and Their Combination Plus Paclitaxel in Women with HER2-Positive Primary Breast Cancer.

Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, Aura C, De Azambuja E, Gomez H, Dinh P, Fauria K, Van Dooren V, Paoletti P, Goldhirsch A, Chang T-W, Lang I, Untch M, Gelber RD, Piccart-Gebhart M, on Behalf of the NeoALTTO Study Team. Vall d'Hebron University Hospital, Barcelona, Spain; FSS Ltd, Kincraig, United Kingdom; University Hospital Kiel, Germany; Breast Cancer Center Vall d'Hebron University Hospital and SOLTI (Spanish Breast Cancer Research Group), Barcelona, Spain; Institut Jules Bordet and Breast European Adjuvant Study Team, Brussels, Belgium; Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Breast International Group, Brussels, Belgium; SOLTI (Spanish Breast Cancer Research Group), Barcelona, Spain; Breast European Adjuvant Study Team, Brussels, Belgium; GlaxoSmithKline, Collegeville, PA; European Institute of Oncology, Milan, Italy; National Cheng Kung University Hospital, Tainan, Taiwan; National Institute of Oncology, Budapest, Hungary; Academic Hospital of the University Charite, Berlin, Germany; Dana-Farber Cancer Institute, Boston, MA; Institut Jules Bordet, Brussels, Belgium

Background: The addition of trastuzumab to neoadjuvant chemotherapy has significantly improved pathological complete response (pCR) in patients with HER2-positive early breast cancer (BC). Lapatinib, a dual HER2/EGFR tyrosine kinase inhibitor, combined with chemotherapy has significantly improved progression free survival in patients with metastatic HER2-positive BC. Additionally, lapatinib combined with trastuzumab improved disease-free and overall survival in patients with metastatic HER2-positive BC. The NeoALTTO trial is testing the efficacy of lapatinib, trastuzumab or their combination together with paclitaxel when given as neoadjuvant therapy in patients with HER2-positive BC.
Material and Methods: NeoALTTO is an international, multicenter, randomized study comparing the efficacy of lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant lapatinib and trastuzumab plus paclitaxel given as neoadjuvant treatment for HER2-positive primary BC. From January, 2008, to December, 2009, 455 patients from 99 participating sites were randomized to receive either lapatinib 1500 mg/d (154 pts), or trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly (149 pts), or lapatinib 1000 mg/d with trastuzumab for a total of 6 weeks (152 pts). After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel 80 mg/mē for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). After surgery, patients received 3 cycles of adjuvant FEC followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy). The primary objective of the study is to evaluate and compare among the three arms the rate of pCR, defined as the absence of invasive cancer in the breast at the time of surgery. Secondary objectives include objective response rate, safety, pathologic node-negative status, rate of conversion to breast conservation, disease-free survival and overall survival. All patients underwent tumor biopsies for comparative pharmacodynamic analyses before beginning therapy and on day 15 of the biological therapy window. A subset of patients also participated in PET/CT and circulating tumor cells substudies.
Results: pCR was significantly higher in the combination arm (lapatinib plus trastuzumab) compared with either trastuzumab or lapatinib alone (51.3% vs. 29.5% vs. 24.7%, respectively; p < 0.01 for both). Corresponding objective (clinical) response rates at 6 weeks (biological window) were 67.1%, 30.2% and 52.6%, and those at surgery were 80.3%, 70.5% and 74.0%. There were neither major cardiac dysfunctions nor any toxic deaths during the neoadjuvant phase. There was increased, but manageable, toxicity (mainly diarrhea and liver enzyme alterations) in the lapatinib arms.
Conclusions: The primary objective of NeoALTTO was achieved for the combination. Dual blockade of HER2 pathway is a valid concept. Data for correlation between pCR and DFS and/or OS will be available in the future.

Friday, December 10, 2010 10:00 AM

General Session 3 (9:30 AM-11:30 AM)

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