The addition of tucatinib to trastuzumab and capecitabine significantly extended PFS among patients with locally advanced unresectable or metastatic HER2-positive breast cancer, according to topline results of the randomized HER2CLIMB trial.
Tucatinib (Seattle Genetics) is an oral small molecule tyrosine kinase inhibitor that is highly selective for HER2.
The double-blind, placebo-controlled HER2CLIMB trial enrolled 612 patients with locally advanced or metastatic HER2-positive breast cancer who received prior treatment with trastuzumab (Herceptin, Genentech), pertuzumab (Perjeta, Genentech) and ado-trastuzumab emtansine (Kadcyla, Genentech).
Nearly half (47%) of patients had brain metastases at baseline.
Researchers randomly assigned patients 2:1 to trastuzumab and capecitabine with or without tucatinib.
PFS assessed by blinded independent central review among the first 480 patients enrolled served as the primary endpoint. Results showed a significant PFS benefit with the addition of tucatinib (HR = 0.54; 95% CI, 0.42-0.71).
The trial also met its key secondary endpoints at interim analysis, showing tucatinib prolonged OS (HR = 0.66; 95% CI, 0.5-0.88) and also extended PFS among patients with brain metastases at baseline (HR = 0.48; 95% CI, 0.34-0.69).
“There is significant unmet medical need following treatment with trastuzumab, pertuzumab and [ado-trastuzumab emtansine among] patients with metastatic HER2-positive breast cancer,” Roger Dansey, MD, chief medical officer at Seattle Genetics, said in a company-issued press release. “The addition of tucatinib to the commonly used doublet of trastuzumab and capecitabine represents a potential significant clinical advance for patients with metastatic HER2-positive breast cancer, importantly including those with brain metastases.”
The trial will be unblinded and patients assigned the control regimen will be offered tucatinib, Dansey said.
The company expects to submit a new drug application to the FDA in early 2020.
The combination of tucatinib, trastuzumab and capecitabine appeared generally well-tolerated and exhibited a manageable safety profile. The most common adverse events among tucatinib-treated patients included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue and vomiting.
Grade 3 or higher adverse events that occurred more frequently in the tucatinib arm included diarrhea (12.9% vs. 8.6%), increased aspartate aminotransferase (4.5% vs. 0.5%) and increased alanine aminotransferase (5.4% vs. 0.5%).
A similar percentage of patients in the experimental and control groups discontinued treatment due to adverse events (5.7% vs. 3%).
Additional results from HER2CLIMB are scheduled for presentation in December at San Antonio Breast Cancer Symposium.