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

Clin Cancer Res. 2021 Mar 1;27(5):1463-1475. doi: 10.1158/1078-0432.CCR-20-3555. Epub 2020 Dec 22.


Purpose: Approved therapies for EGFR exon 20, ERBB2 mutations, and NRG1 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 EGFR exon 20 insertion mutations, ERBB2 mutations and amplification, and NRG1 fusions were tested in vitro and in vivo 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 in vitro by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. In vivo, 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 ERBB2 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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / drug therapy*
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / pathology
  • Adult
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia / physiopathology*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy
  • Mutation
  • Phosphorylation
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays


  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2