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

Purpose: Approved therapies for exon 20, mutations, and 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.

Experimental Design: Novel and existing patient-derived cell lines and xenografts harboring exon 20 insertion mutations, mutations and amplification, and fusions were tested and with tarloxotinib to determine its impact on cancer cell proliferation, apoptosis, and cell signaling.

Results: Tarloxotinib-E inhibited cell signaling and proliferation in patient-derived cancer models by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. , 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 exon 20 p.A775_G776insYVMA mutation demonstrated a dramatic clinical response to tarloxotinib.

Conclusions: 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.