Clinical Pearls & Morning Reports
Murthy et al. conducted the HER2CLIMB trial, which 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. Read the NEJM Original Article here.
Q: What is the current standard-of-care for patients with HER2-positive metastatic breast cancer?
A: Standard-of-care treatment for patients with HER2-positive metastatic breast cancer is first-line trastuzumab plus pertuzumab and a taxane, followed by second-line trastuzumab emtansine for patients who have disease progression. After progression during treatment with trastuzumab emtansine, no single regimen is considered the standard of care; commonly used regimens include tyrosine kinase inhibitors such as lapatinib with trastuzumab or capecitabine, trastuzumab with chemotherapy, or participation in a clinical trial.
Q: What is tucatinib?
A: Tucatinib is an investigational, oral tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of epidermal growth factor receptor, which may alter the toxicity profile. In a phase 1b dose-escalation trial, tucatinib in combination with trastuzumab and capecitabine showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.
A: At 1 year, the estimated progression-free survival was 33.1% (95% confidence interval [CI], 26.6 to 39.7) in the tucatinib-combination group and 12.3% (95% CI, 6.0 to 20.9) in the placebo-combination group, and the median duration of progression-free survival was 7.8 months (95% CI, 7.5 to 9.6) and 5.6 months (95% CI, 4.2 to 7.1), respectively. The risk of disease progression or death, as assessed by means of blinded independent central review in the primary endpoint analysis population, was 46% lower in the tucatinib-combination group than in the placebo-combination group (hazard ratio, 0.54; 95% CI, 0.42 to 0.71; P<0.001). At 2 years, the estimated overall survival was 44.9% (95% CI, 36.6 to 52.8) in the tucatinib-combination group and 26.6% (95% CI, 15.7 to 38.7) in the placebo-combination group, and the median duration of overall survival was 21.9 months (95% CI, 18.3 to 31.0) and 17.4 months (95% CI, 13.6 to 19.9), respectively. The tucatinib combination was associated with a significantly lower risk of disease progression or death than the placebo combination among patients with metastatic HER2-positive breast cancer with brain metastases.
A: The most common adverse events observed among the patients in the tucatinib-combination group were diarrhea, palmar–plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting; most events were of grade 1 or 2. The most common adverse events of grade 3 or higher observed among the patients in the tucatinib-combination group were palmar–plantar erythrodysesthesia syndrome, diarrhea, elevations in alanine aminotransferase and aspartate aminotransferase levels, and fatigue.