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

Sénologie - Publié le 22/01/2020 par Ilfad Blazevic

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 previ-
ously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had
or did not have brain metastases, to receive either tucatinib or placebo, in combina-
tion 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, pro-
gression-free survival among patients with brain metastases, confirmed objective re-
sponse 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 ClinicalTrials.gov number, NCT02614794.)

Source : NEJM 2019