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N Engl J Med. 2019 Dec 11. doi: 10.1056/NEJMoa1914609. [Epub ahead of print]

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.

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From M.D. Anderson Cancer Center, Houston (R.K.M., G.H.); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (S. Loi); the Royal Marsden NHS Foundation Trust, London (A.O.), and Edinburgh Cancer Research Centre, Edinburgh (D.C.) - both in the United Kingdom; Winship Cancer Institute, Atlanta (E.P.); Sarah Cannon Research Institute/Tennessee Oncology-Nashville (E.H.) and Vanderbilt University Medical Center (V.A.), Nashville; University of California, Los Angeles, Medical Center-Jonsson Comprehensive Cancer Center, Los Angeles (S.A.H., D.S.), and Stanford Comprehensive Cancer Institute, Palo Alto (M.P.) - both in California; Dana-Farber Cancer Institute, Boston (N.U.L., I.K., E.P.W.); University of Colorado Cancer Center, Aurora (V.B.); Duke Cancer Institute, Durham (C.A.), and University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (L.A.C.) - both in North Carolina; University Health Network, Princess Margaret Cancer Centre, Toronto (P.L.B.), and British Columbia Cancer, Vancouver (K.G.) - both in Canada; Hospital Universitario Vall D'Hebron, Barcelona (M.O.); Sygehus Lillebaelt-Vejle Sygehus, Vejle, Denmark (E.J.); Centre Léon Bérard, Lyon, France (T.B.); Rambam Health Care Campus, Haifa, Israel (S.S.S.); Universitaetsklinikum Hamburg-Eppendorf, Hamburg (V.M.), and German Breast Group, Neu-Isenburg (S. Loibl) - both in Germany; Hospital Cuf Descobertas R. Mário Botas, Lisbon, Portugal (S.B.); Cliniques Universitaires Saint-Luc, Brussels (F.P.D.); Third Medical Department, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, and Cancer Cluster Salzburg, Salzburg, Austria (R.G.); Istituto Europeo di Oncologia, IRCCS, University of Milan, Milan (G.C.); and Seattle Genetics, Bothell, WA (M.C.P.-W., L.W., W.F.).



Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.


We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.


Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.


In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB number, NCT02614794.).


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