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

Abstract

BACKGROUND 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. METHODS 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. RESULTS 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 placebocombination 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. CONCLUSIONS 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.

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

“…The HER2CLIMB trial evaluated the addition of tucatinib to trastuzumab and capecitabine in patients with HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1. The one-year PFS rate was 33.1% for the tucatinib-containing regimen and 12.3% for the control regimen (HR of 0.54, 95% CI of 0.42-0.71; p < 0.001), and the median PFS rates were 7.8 and 5.6 months, respectively, with the primary end point thus being met [56].…”

Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models

“…These characteristics are consistent with tucatinib's observed safety and activity in early clinical trials in patients with HER2 þ MBC, including the phase I ONT-380-005 study (NCT02025192) in combination with trastuzumab or trastuzumab and capecitabine (26) and the phase I ONT-380-004 study (NCT01983501) combining tucatinib with Ado-Trastuzumab Emtansine in patients with HER2 þ MBC with or without brain metastases (28). Furthermore, the outcome of an international, randomized, double-blind trial comparing the combination of tucatinib plus trastuzumab and capecitabine to placebo plus trastuzumab and capecitabine was recently reported (47). The results of this trial demonstrated the addition of tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes in patients with heavily pretreated HER2-positive MBC, including those with brain metastases.…”

The Agonist of JWA Gene JAC1 Suppresses Proliferation of Breast Cancer Through the JWA/p38/SMURF1/HER2 Signaling

“…The current HER2-targeted therapies (trastuzumab, pertuzumab and lapatinib) have been approved for clinical treatment of HER2-positive BC and largely improved prognosis of HER2-positive cases [34]. Unfortunately, the unavoidable side effects induced by the therapies and drug resistance are always accompanied during the therapeutic period and have become the biggest challenge in clinical application [35,36].…”