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.
View: Text | PDF | Corrigendum
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

×

Figure 3

Sensitivity of HNSCC cell lines to evofosfamide is associated with expression of proliferation-related genes.

Options: View larger image (or click on image) Download as PowerPoint
Sensitivity of HNSCC cell lines to evofosfamide is associated with expre...
(A) Head and neck squamous cell carcinoma (HNSCC) cell lines dichotomized by the arithmetic mean of anoxic evofosfamide IC50 values into sensitive and resistant groups for differential expression analysis using RNA sequencing. Data are defined as in Figure 1B. (B) Unsupervised hierarchical clustering of HNSCC cell lines according to their expression of the top 200 most differentially expressed genes (by P value) between evofosfamide-sensitive and evofosfamide-resistant cell lines. The gene list was defined using limma and the clustering performed using the ward.D method with Euclidean distance. (C) Statistical overrepresentation of gene ontology (GO) terms (assessed using PANTHER [ref. 80]; left) or molecular pathways (assessed using GeneSetDB [ref. 81], right) among the 200 genes most differentially expressed between evofosfamide-sensitive and evofosfamide-resistant cell lines (as per panel B). False discovery rates (FDRs) arising from Benjamini–Hochberg adjustment of P values from Fisher’s exact tests are shown for the 10 most significant GO and pathway findings. Dashed lines denote the 5% FDR.