A combination of three drugs, lapatinib (Tykerb?/Tyverb? , GlaxoSmithKline), an orally active, reversible, small-molecule tyrosine kinase inhibitor that potently inhibits both HER1 and HER2 tyrosine kinase activity, trastuzumab (Herceptin?, Genentech), a humanized monoclonal antibody directed against HER2, and paclitaxel (Taxol? , Bedford Laboratories/Bristol-Myers Squibb Company) significantly improved tumor response rates than either agent alone among patients with HER2-positive breast cancers, according to data presented at the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 8-12, 2010

These results are from the NeoALTTO Trial , an international, open label multicenter, randomized phase III study comparing the efficacy of neoadjuvant lapatinib plus paclitaxel versus trastuzumab plus paclitaxel versus a combination of all three agents as neoadjuvant chemotherapy among 455 patients with HER2- (ErbB2) positive breast cancer.

In this trial, patients were randomized to receive either lapatinib 1500 mg daily, trastuzumab 4 mg/kg iv load followed by 2 mg/kg iv weekly, or lapatinib 1000 mg daily with trastuzumab 4 mg/kg iv load followed by 2 mg/kg iv weekly for a total of 6 weeks. After a biological window, patients on monotherapy arms continued on the same targeted therapy plus weekly paclitaxel 80 mg/m2 for a further 12 weeks, up to definitive surgery. In the combination arm, patients received lapatinib 750 mg daily in combination with trastuzumab 2 mg/kg IV plus weekly paclitaxel 80mg/m2 IV for a further 12 weeks, up to definitive surgery.

After surgery, patients received three courses of adjuvant chemotherapy with FEC followed by the same targeted therapy as in the biological window of the neoadjuvant setting for a further 34 weeks (in the combination arm, lapatinib dose was1000 mg daily in combination with trastuzumab). The last patient was randomised in December 2009. The NeoALTTO trial was organised by BIG (Breast International Group) and the Spanish-based SOLTI (SOLid Tumour Intensification) Group.

Lead researcher Jos? Baselga, M.D., Ph.D., chief of the division of hematology and oncology and associate director of the Massachusetts General Hospital Cancer Center, said early data indicate a 50% rate of pathological complete remission compared with 20% for either agent alone.

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?This study suggests that a dual blockade against HER2 is an efficient way to target HER2-positive breast tumors and that lapatinib adds to trastuzumab. While further research is ongoing, our results indicate that we are on the right track to improve the therapy of HER2-positive disease,? Baselga said.

?It has been suggested in basic science research and smaller clinical trials that the combination of these therapies would be more effective than either alone, but this is the first time it has been shown in a large clinical trial setting,? said Baselga.

At the San Antonio symposium, Baselga presented the primary outcome of tumor rate after surgery, as well as the secondary outcomes of objective response rate, safety, pathologic node-negative status, rate of conversion to breast conservation, disease-free survival and overall survival.

For more information:
de Azambuja E, Cardoso F, Meirsman L, Straehle C, Dolci S, Vantongelen K, Piccart-Gebhart M. The new generation of breast cancer clinical trials: the right drug for the right target Bull Cancer. 2008 Mar;95(3):352-7.

Clinical trial
Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study.

Photo by ? SABCS/Todd Buchanan 2010

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