FDA Grants Breakthrough Therapy Designation to Tucatinib in Combination Therapy for HER2-Positive Breast Cancer

Seattle Genetics recently announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to tucatinib, in combination with trastuzumab and capecitabine, for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1). The results of the HER2CLIMB clinical trial on which this designation is based were announced in October 2019, and additional data were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS)¹ and simultaneously published in The New England Journal of Medicine.² Tucatinib is an oral, small-molecule tyrosine kinase inhibitor that is highly selective for HER2.

Key Study Findings

HER2CLIMB is a multinational, randomized (2:1), double-blind, placebo-controlled, active comparator clinical trial. The primary endpoint was progression-free survival per Response Evaluation Criteria in Solid Tumors, version 1.1, as determined by blinded independent central review in the first 480 patients enrolled. A total of 612 patients were enrolled to support the analyses of key secondary endpoints, including overall survival, progression-free survival in patients with brain metastases at baseline, and confirmed objective response rate.

For progression-free survival, the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.54; 95% confidence interval (CI) = 0.42–0.71; P < .00001). The trial met the two key secondary endpoints at interim analysis. The tucatinib arm demonstrated an improvement in overall survival, with a 34% reduction in the risk of death (HR = 0.66; 95% CI = 0.50–0.88; P = .0048), compared with the control arm. For patients with brain metastases at baseline, the tucatinib arm also demonstrated superior progression-free survival, with a 52% reduction in the risk of disease progression or death, compared with the control arm (HR = 0.48; 95% CI = 0.34–0.69; P < .00001).

Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated. The most common adverse events occurring in more than 20% of patients in the tucatinib arm vs the control arm included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. ■

DISCLOSURE: The study authors’ disclosure information can be found at abstractsonline.com.

REFERENCES

1. Murthy R, et al: 2019 San Antonio Breast Cancer Symposium. Abstract GS1-01. Presented December 11, 2019.

2. Murthy RK, Loi S, Okines A, et al: Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. December 11, 2019 (early release online).