Abstract 4222: Tucatinib, a selective small molecule HER2 inibitor, is active in HER2 mutant driven tumors

Abstract

Abstract Tucatinib is an investigational, orally dosed, small molecule tyrosine kinase inhibitor that is highly selective for the kinase domain of HER2 without significant inhibition of EGFR. In this report, we describe the activity of tucatinib alone and in combination with trastuzumab in multiple HER2 mutant driven PDX models. Tucatinib was tested in 6 HER2 mutant PDX tumor models derived from colorectal, non-small cell lung cancer, gall bladder and gastric cancers with L755S, V77L or S310Y mutations. MCF-10A cells were engineered to express the L755S and V777L HER2 activating point mutations and the potency of tucatinib was evaluated in each of these cell lines using HER2 autophosphorylation as an endpoint. The activity of tucatinib was also evaluated in G776V_G/C and G776_YVMA in frame exon 20 insertion mutations, including the G776V_G/C mutant non-small cell lung cancer line NCI-H1781 using both cellular signaling and cell proliferation as endpoints. Tucatinib significantly inhibited tumor growth in 5 of the 6 HER2 point mutant PDX models, whereas trastuzumab alone significantly inhibited tumor growth in 1 of 6 models and the combination of both drugs was significantly active in all HER2 mutant models. Tucatinib inhibited the phosphorylation of HER2 in a L755S mutant MCF-10A cell line and inhibited the growth of 3 L755S mutant tumor models derived from colorectal, gastric and non-small cell lung cancer. Tucatinib also potently inhibited the phosphorylation of HER2 in a V777L mutant MCF-10A cell line, and in a colorectal PDX model containing a V777L mutation, tucatinib alone or in combination with trastuzumab induced tumor regressions. In two PDX models containing the S310Y extracellular domain mutation of HER2, tucatinib alone, or in combination with trastuzumab, resulted in tumor growth delays. In exon 20 insertion mutant derived cell lines, tucatinib inhibited HER2 phosphorylation, but not EGFR phosphorylation, and inhibited the phosphorylation of HER2, HER3, Erk1/2, MEK1 and AKT in the G776V_G/C HER2 mutant NCI-H1781 cell line. These data demonstrate that tucatinib, a highly potent and selective inhibitor of HER2 signaling without significant inhibition of EGFR, is active in multiple HER2 mutant driven tumor models. Importantly, tucatinib is active in models containing the L755S HER2 mutation which has been associated with lapatinib resistance preclinically (1), and trastuzumab resistance clinically (2). Taken together, these results support the idea that HER2 selective inhibition by tucatinib can block oncogenic signaling elicited by mutant HER2, and that it could potentially provide clinical benefit in patients with cancers with activating HER2 mutations.