Seattle Genetics announced positive topline results from the HER2CLIMB trial, which compared tucatinib in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer. Patients had previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1), and 47 percent of the patients enrolled in the trial had brain metastases at the time of enrollment.
HER2CLIMB was a global randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial and enrolled a total of 612 patients. The trial met the primary endpoint of progression-free survival (PFS), showing that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46% reduction in the risk of disease progression or death. The trial also 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 compared to trastuzumab and capecitabine alone. For patients with brain metastases at baseline, the tucatinib arm also demonstrated superior PFS, with a 52% reduction in the risk of disease progression or death compared to those who received trastuzumab and capecitabine alone. Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated with a manageable safety profile. The most frequent adverse events in the tucatinib arm included diarrhea, palmar-plantar erythrodysesthesia syndrome (PPE), nausea, fatigue, and vomiting.
Based on these results, the company plans to submit a New Drug Application (NDA) to the FDA in the first quarter of 2020.
About HER2-Positive Breast Cancer
Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019. Between 15 and 20 percent of breast cancer cases worldwide are HER2-positive. Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer. In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver. Approximately 30 to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time. Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on T-DM1.
Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.