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 1

Potency and hypoxic selectivity of evofosfamide and reference agents for head and neck squamous cell carcinoma (HNSCC) cell lines.

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Potency and hypoxic selectivity of evofosfamide and reference agents for...
(A) Chemical structures of evofosfamide, its DNA crosslinking metabolite bromo-iso-phosphoramide mustard (Br-IPM), and the comparator hypoxia-activated prodrugs PR-104A (a dinitrobenzamide) and SN30000 (a benzotriazine di-N-oxide). (B) Antiproliferative activity of evofosfamide — measured as the concentration required for 50% inhibition of cell growth (IC50) — in 21 HNSCC cell lines assessed by sulforhodamine B assay after 4-hour drug exposure under anoxia (N2) or ambient oxygen (air) followed by 5-day regrowth, with hypoxia selectivity represented as the Air-N2 IC50 quotient. The Air/N2 ratio is plotted as the mean ± SEM from 3 or more intraexperiment quotients calculated from anoxic and normoxic assays performed on the same days. Boxes represent the median and interquartile range, whereas whiskers mark the minimum and maximum IC50 determinations from 3 or more independent experiments. Dashed lines denote the mean IC50 values for the cell line panel. (C) Comparison of the in vitro antiproliferative potency and hypoxic selectivity of evofosfamide (evo), PR-104A, and SN30000 in 21 HNSCC cell lines. Data points denote mean IC50 values for individual cell lines computed from 3 or more experiments, with IC50 values and Air/N2 IC50 quotients defined as per panel B. Horizontal lines mark the median values. The statistical significance of differences in the potency and selectivity of drugs was assessed by 1-way ANOVA with Dunnett’s correction. (D) Comparison of the antiproliferative potency (as IC50 under N2 or air) of evofosfamide in HNSCC cell lines derived from primary (n = 15) or nodal/recurrent (n = 6) lesions. Statistical significance of differences in IC50 values between these groups was assessed by Mann-Whitney test. (E) Comparison of the pattern of HNSCC cell line sensitivity (as IC50 values) to evofosfamide and to Br-IPM, cisplatin, 5-FU, PR-104A, and SN30000 under anoxia. IC50 values were defined as per panel B and data points correspond to individual cell lines. Axes are linear and functions are Pearson’s correlations.