Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

Stephen Mf Jamieson, Peter Tsai, Maria K. Kondratyev, Pratha Budhani, Arthur Liu, Neil N. Senzer, E. Gabriela Chiorean, Shadia Jalal, John J. Nemunaitis, Dennis Kee, Avik Shome, Way W. Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M. Kakadia, Nicholas S. Knowlton, Courtney Rh Lynch, Cho R. Hong, Tet Woo Lee, Reidar A. GrénmanLaura Caporiccio, Trevor D. McKee, Mark Zaidi, Sehrish Butt, Andrew Mj Macann, Nicholas P. McIvor, John M. Chaplin, Kevin O. Hicks, Stefan K. Bohlander, Bradly G. Wouters, Charles P. Hart, Cristin G. Print, William R. Wilson, Michael A. Curran, Francis W. Hunter

Research output: Contribution to journalArticle

12 Scopus citations


Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.

Original languageEnglish (US)
JournalJCI insight
Issue number16
StatePublished - Aug 23 2018


  • Cancer
  • Head & neck cancer
  • hypoxia
  • Oncology
  • Therapeutics

Fingerprint Dive into the research topics of 'Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma'. Together they form a unique fingerprint.

  • Cite this

    Jamieson, S. M., Tsai, P., Kondratyev, M. K., Budhani, P., Liu, A., Senzer, N. N., Chiorean, E. G., Jalal, S., Nemunaitis, J. J., Kee, D., Shome, A., Wong, W. W., Li, D., Poonawala-Lohani, N., Kakadia, P. M., Knowlton, N. S., Lynch, C. R., Hong, C. R., Lee, T. W., ... Hunter, F. W. (2018). Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma. JCI insight, 3(16). https://doi.org/10.1172/jci.insight.122204