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 4

A proliferation expression signature correlates with evofosfamide sensitivity in head and neck squamous cell carcinoma (HNSCC) cell lines.

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A proliferation expression signature correlates with evofosfamide sensit...
(A) The workflow for functional genomic screens for modifiers of evofosfamide or Br-IPM sensitivity. SpCas9, Streptococcus pyogenes Cas9. (B) Enrichment (positive selection) or depletion (negative selection) of single guide RNA (sgRNA) in evofosfamide- and Br-IPM-treated UT-SCC-74B cells (2 replicates per condition). The screen was deconvoluted using the RIGER method (83) with weighted-sum aggregation to output gene-level P values that were adjusted using the Benjamini-Hochberg method. (C) Unsupervised hierarchical clustering (ward.D method with Euclidean distance) of HNSCC cell lines according to their expression (measured by RNAseq) of a published tumor proliferation metagene (57). Of 61 genes in the proliferation cluster, 49 were expressed in HNSCC cells. The resulting proliferation metagene class assignments and whether cell lines were derived from primary, nodal, or recurrent lesions are indicated. (D) Differential in vitro sensitivity to evofosfamide per antiproliferative IC50 assay in HNSCC cell lines separated by proliferation metagene status, where the grouping of cell lines as proliferationhi or proliferationlo was accomplished by assignment of cell lines to binary clusters defined by unsupervised hierarchical clustering according to expression values of the metagene as shown in C. Box plots show the mean and interquartile range, whereas whiskers show the maximum and minimum IC50 values for metagene-high (n = 13) and metagene-low (n = 8) cell lines (≥3 independent experiments). Statistical significance was assessed by Mann–Whitney test.