Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma
Stephen M.F. Jamieson, … , Michael A. Curran, Francis W. Hunter
Stephen M.F. Jamieson, … , Michael A. Curran, Francis W. Hunter
Published August 23, 2018
Citation Information: JCI Insight. 2018;3(16):e122204. https://doi.org/10.1172/jci.insight.122204.
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Research Article Oncology Therapeutics

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

Abstract

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.

Authors

Stephen M.F. Jamieson, Peter Tsai, Maria K. Kondratyev, Pratha Budhani, Arthur Liu, Neil N. Senzer, E. Gabriela Chiorean, Shadia I. Jalal, John J. Nemunaitis, Dennis Kee, Avik Shome, Way W. Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M. Kakadia, Nicholas S. Knowlton, Courtney R.H. Lynch, Cho R. Hong, Tet Woo Lee, Reidar A. Grénman, Laura Caporiccio, Trevor D. McKee, Mark Zaidi, Sehrish Butt, Andrew M.J. 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

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Figure 8

Partial response (PR) to evofosfamide monotherapy in an example head and neck squamous cell carcinoma (HNSCC) case.

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Partial response (PR) to evofosfamide monotherapy in an example head and...
This 71-year-old woman presented with a recurrent, poorly differentiated squamous cell carcinoma (SCC) of the neck and oral cavity metastatic to lymph nodes that was previously treated with cetuximab, radiotherapy, and surgery. At baseline, the coronal CT (left panel) shows recurrent tumor centered in the left oropharynx, extending from the region of the palate to the lateral and posterior pharyngeal wall, with inferior extension into the hypopharynx. The patient received evofosfamide (480 mg/m2 qw × 3 per 28-day cycle), with PR noted at cycles 2 (right panel) and 4. Disease progression based on target lesions was observed at cycle 6.