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 2

Enzymatic activation of evofosfamide and its contribution to antiproliferative activity in a subset of 15 cultured head and neck squamous cell carcinoma (HNSCC) cell lines.

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Enzymatic activation of evofosfamide and its contribution to antiprolife...
(A) Route of metabolic activation of evofosfamide in hypoxic tumor cells by enzymatic 1-electron reduction. As described in literature (39), evofosfamide undergoes enzyme-catalyzed 1-electron reduction to a transient radical anion that fragments to release Br-IPM and the free 2-nitroimidazole trigger (“Trigger-H”). In the presence of oxygen, the radical anion is back-oxidized to evofosfamide, preventing accumulation of Br-IPM and thus conferring hypoxic selectivity. Fragmentation at the 1-electron (radical anion) stage competes with further reduction to the corresponding hydroxylamine, which also fragments to release Br-IPM but does not generate Trigger-H. Halide exchange results in the conversion of Br-IPM to more stable Cl-IPM. Br-IPM, Cl-IPM, and Trigger-H are thus all diagnostic of the reductive activation of evofosfamide. Frag, fragmentation. (B) Comparison of the facility of reductive activation of evofosfamide in HNSCC cell lines by liquid chromatography–tandem mass spectrometry (LC-MS/MS) measurement of intracellular Br-IPM, Cl-IPM, and Trigger-H concentrations at the endpoint of 1-hour exposures to 30 μM evofosfamide under anoxia. Data are the mean ± range from 2 independent determinations. (C) Multiple linear regression of measured evofosfamide antiproliferative activity (as the concentration required for 50% inhibition of cell growth, IC50) in 15 HNSCC cell lines under anoxia compared to IC50 values predicted in the same lines using log Br-IPM IC50 under anoxia as a measure of sensitivity to the active metabolite and the log of the sum of the intracellular concentrations of Br-IPM and Cl-IPM formed from evofosfamide (i.e., the values plotted in panel B) as a measure of its reductive metabolism.