BACKGROUND: Up to 50% of patients with advanced or metastatic HER2-positive breast cancer may have brain metastases, for which effective treatment options are limited. A phase 1b dose-escalation clinical trial of tucatinib, an oral tyrosine kinase inhibitor, in combination with trastuzumab and capecitabine showed antitumor activity in patients with HER2-positive breast cancer, including patients with brain metastases. In a new study, researchers evaluated the use of tucatinib plus trastuzumab and capecitabine in patients who previously received trastuzumab, pertuzumab, and trastuzumab emtansine for the treatment of metastatic HER2-positive breast cancer. In December 2019, the US Food and Drug Administration granted tucatinib, in combination with trastuzumab and capecitabine, a breakthrough therapy designation for this patient population.
METHODS: HER2CLIMB was a randomized, double-blind, placebo-controlled phase 2 clinical trial that included 612 patients with unresectable locally advanced or metastatic HER2-postive breast cancer, some of whom had brain metastases. The patients were randomized in a 2:1 ratio to trastuzumab and capecitabine plus tucatinib or to placebo.
In all, 47.5% of the patients had brain metastases at baseline. Tucatinib was administered orally at 300 mg twice daily during each 21-day cycle. In both cohorts, the patients received capecitabine 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle, and trastuzumab 8 mg/kg intravenously on day 1 of cycle 1, followed by 6 mg/kg thereafter on day 1 of each 21-day cycle. The primary end point was progression-free survival (PFS). The secondary end points included overall survival, PFS in patients with brain metastases, and tolerability.
RESULTS: The tucatinib triplet led to a 46% risk reduction for disease progression or death compared with trastuzumab and capecitabine, with a median PFS of 7.8 months and 5.6 months, respectively. The 1-year PFS rates were 33.1% and 12.3%, respectively. Among patients with brain metastases at baseline, the risk for disease progression or death was reduced by 52% in the tucatinib arm, and the median PFS was 7.6 months in the tucatinib arm and 5.4 months in the placebo arm. The 1-year PFS rates were 24.9% and 0%, respectively. The median overall survival was 21.9 months in the tucatinib arm versus 17.4 in the placebo arm. The 2-year overall survival rates were 44.9% versus 26.6%, respectively.
The tucatinib-based regimen was generally well-tolerated, with mostly low-grade adverse events. Grade ≥3 adverse events were 55.2% in the tucatinib arm versus 48.7% in the placebo arm. Diarrhea was the most common all-grade event in both arms; grade ≥3 diarrhea was 12.9% and 8.6%, respectively. Liver transaminase levels were higher in the tucatinib arm, including grade ≥3 aspartate aminotransaminase (4.5%) and alanine aminotransaminase (5.4%). However, these were mostly low-grade, transient, and reversible events.
Source: Schuster Murthy RS, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.