Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes.

Abstract

Approved therapies for <i>EGFR</i> exon 20, <i>ERBB2</i> mutations, and <i>NRG1</i> fusions are currently lacking for non-small cell lung cancer and other cancers. Tarloxotinib is a prodrug that harnesses tumor hypoxia to generate high levels of a potent, covalent pan-HER tyrosine kinase inhibitor, tarloxotinib-effector (tarloxotinib-E), within the tumor microenvironment. This tumor-selective delivery mechanism was designed to minimize the dose-limiting toxicities that are characteristic of systemic inhibition of wild-type EGFR. Novel and existing patient-derived cell lines and xenografts harboring <i>EGFR</i> exon 20 insertion mutations, <i>ERBB2</i> mutations and amplification, and <i>NRG1</i> fusions were tested <i>in vitro</i> and <i>in vivo</i> with tarloxotinib to determine its impact on cancer cell proliferation, apoptosis, and cell signaling. Tarloxotinib-E inhibited cell signaling and proliferation in patient-derived cancer models <i>in vitro</i> by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. <i>In vivo</i>, tarloxotinib induced tumor regression or growth inhibition in multiple murine xenograft models. Pharmacokinetic analysis confirmed markedly higher levels of tarloxotinib-E in tumor tissue than plasma or skin. Finally, a patient with lung adenocarcinoma harboring an <i>ERBB2</i> exon 20 p.A775_G776insYVMA mutation demonstrated a dramatic clinical response to tarloxotinib. Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor versus normal tissue, and this activity can translate into clinical activity in patients.