BOTHELL, Wash.—A new antibody-drug conjugate crafted by the researchers at Seattle Genetics has delivered positive top-line results from the HER2CLIMB trial, a randomized, double-blind, placebo-controlled, active comparator pivotal trial in patients with locally advanced unresectable or metastatic HER2-positive breast cancer. By combining tucatinib, an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2, with trastuzumab and capecitabine, as compared to the previously tested combination of trastuzumab and capecitabine alone, researchers have found significant promise.
Tucatinib has been a fascinating candidate since its discovery by Array BioPharma. It rapidly advanced to Phase 1 testing where it was tested as a single agent in HER2+ cancers. After partnering with Cascadian Therapeutics, they then tried it in combination with T-DM1, or capecitabine/trastuzumab, in Phase 1b studies, then advanced tucatinib into the pivotal HER2CLIMB trial with capecitabine/trastuzumab based on the Phase 1b data. The drug was tested in HER2+ patients based on its mechanism of operation and selectivity for HER2. Seattle Genetics acquired Cascadian Therapeutics in March 2018, thus securing global rights to tucatinib and its promising late-stage metastatic breast cancer potential.
“Dual targeting of HER2 through combinations of two different HER2-targeted antibodies or through use of therapies with complementary mechanisms of action (i.e., a HER2-targeted antibody and a TKI), has been shown to improve outcomes in patients with HER2+ metastatic breast cancer,” asserts a Seattle Genetics spokesperson. “Randomized controlled clinical trials have shown that combining therapies that target the internal HER2 tyrosine kinase domain and the external HER2 receptor simultaneously may result in improved outcomes for patients with HER2+ metastatic breast cancer.”
Patients in the trial tolerated the tucatinib in combination with trastuzumab and capecitabine with moderate side effects, which included diarrhea, palmar-plantar erythrodysaesthesia syndrome, nausea, fatigue and vomiting. These adverse reactions were consistent with those in the control arm, without thetucatinib.
The trial met the clinical goalpost of progression-free survival (PFS), showing that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46-percent reduction in the risk of disease progression or death. The trial also achieved two key secondary successes: an improvement in overall survival, with a 34-percent reduction in the risk of death compared to trastuzumab and capecitabine alone; and, for patients with brain metastases at the time of the trial, the tucatinib arm also demonstrated superior PFS with a 52-percent reduction in the risk of disease progression or death.
“There is significant unmet medical need following treatment with trastuzumab, pertuzumab and T-DM1 in patients with metastatic HER2-positive breast cancer,” said Dr. Roger Dansey, chief medical officer of Seattle Genetics. “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. Based on these findings, we plan to unblind the trial and offer tucatinib to patients on the control arm. We also plan to submit a New Drug Application to the FDA in the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients.”
While Seattle Genetics isn’t ready to share specific timelines, they are confident that the data point to the potential best-in-class nature of tucatinib and justifies their continued investment in the tucatinib clinical development program. They remain actively working to expand their clinical program to investigate its use in earlier lines of HER2-positive breast cancer, including neoadjuvant settings, as well as other solid tumors. Their clinical program around tucatinib will also include expansion into other areas of breast cancer and solid tumors, including metastatic colorectal cancer, for which the compound has already shown promise.
“In initial results from the Phase 2 MOUNTAINEER trial presented at the 2019 European Society of Medical Oncology, the combination of tucatinib and trastuzumab demonstrated significant activity for heavily pre-treated patients with HER2-positive metastatic colorectal cancer,” says the company spokesperson. “We look forward to developing tucatinib in combination with trastuzumab and other therapies to broaden our understanding of its potential for patients with hard-to-treat cancers.”