Abstract B003: Combinatorial therapies of neratinib for HER2-amplified cancer

Abstract

Activation of HER2 signaling by amplification or overexpression of ERBB2 (HER2) is associated with the development and progression of breast cancer. Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor which selectively inhibits EGFR, HER2 and HER4. In this preclinical study, we explored the therapeutic efficacy of neratinib in combination with other clinically relevant targeted agents for HER2-amplified breast cancer in in vitro and in vivo models. HER2-amplified cell lines BT-474, SK-BR-3, and HCC-1954 were sensitive to neratinib with low nanomolar IC50s. Cell viability and colony formation assays demonstrated synergistic anti-proliferative activity of neratinib in combination with multiple targeted agents, including the MEK inhibitor trametinib, the PI3Ka inhibitor alpelisib, the mTOR inhibitors everolimus and sapanisertib, and CDK4/6 inhibitor palbociclib. We tested combinatorial efficacy of neratinib with everolimus, trametinib, and palbociclib in vivo on five HER2-amplified PDXs (two breast, two colorectal and one gastric-esophageal junction cancer), four derived from patients with previous HER2-targeted therapy. The combination of neratinib with everolimus or trametinib led to at least a 100% increase in median time for tumor doubling in 25% (1 of 4) and 60% (3 of 5) models respectively and was associated with decreased tumor volumes in 50% (2 of 4) and 20% (1 of 5) of the models respectively. The combination of neratinib with palbociclib significantly enhanced antitumor efficacy compared to single agent treatment in all five PDX models. The combination achieved treatment/control volume ratios of 0.03-0.16 and increased time for tumor doubling more than 100% in all five models. Taken together, our results provide solid preclinical evidence for targeting combinatorial therapies of neratinib for HER2-amplified cancer. Citation Format: Ming Zhao, Stephen Scott, Kurt Evans, Erkan Yuca, Turcin Saridogan, Mehmet E Demirhan, Bryce P Kirby, Scott Kopetz, Irmina Diala, Alshad S Lalani, Sarina A Piha-Paul, Funda Meric-Bernstam. Combinatorial therapies of neratinib for HER2-amplified cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B003. doi:10.1158/1535-7163.TARG-19-B003