Tucatinib, an orally bioavailable and HER2 selective small molecule tyrosine kinase inhibitor, is currently being developed for HER2+ metastatic breast cancer in combination with capecitabine + trastuzumab (HER2CLIMB study). In addition to breast cancer, HER2 is amplified in subsets of patients with other malignancies, including gastrointestinal cancers (colorectal, esophageal and gastric cancers). To test whether tucatinib might have utility in treating HER2-amplified cancers originating from the gastrointestinal tract, tucatinib was tested alone, and in combination with trastuzumab, in cell line derived and PDX models of colorectal, esophageal and gastric cancer.
In vitro assays were performed to evaluate the combination of tucatinib and trastuzumab in HER2-amplified cell lines by measuring changes in signal transduction (pHER2, pHER3, pAKT) and cell survival. The in vivo activity of tucatinib (50 mg/kg BID) and trastuzumab (20 mg/kg Q3D) was evaluated alone, or in combination, in established HER2-amplified tumor models, including PDX models of colorectal, esophageal and gastric cancers.
As a single agent, or in combination with trastuzumab, tucatinib demonstrated significant anti-tumor activity, including tumor regressions, in the N87 gastric cancer cell line xenograft model and in PDX models of HER2 amplified colorectal, esophageal and gastric cancers. The combination of tucatinib and trastuzumab was consistently more active than either single agent alone, and resulted in tumor growth inhibition from 85-139%, including complete tumor regressions in HER2+ gastric PDX models.
The activity of tucatinib in HER2-amplified colorectal, esophageal and gastric tumor xenograft models supports the exploration of using tucatinib to treat HER2+ gastrointestinal cancers in the clinical setting. To this end, an open label phase II clinical study combining tucatinib with trastuzumab in HER2+/RAS wild type metastatic colorectal cancer (MOUNTAINEER) has recently been initiated.
Clinical trial identification
Legal entity responsible for the study
S. Peterson: Employee and shareholder of Cascadian Therapeutics, corporate officer of Cascadian Therapeutics. P. de Vries, J. Piasecki, R. Rosler: Employee and shareholder of Cascadian Therapeutics