Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma
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
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
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 6

Efficacy of evofosfamide alone or with radiotherapy in head and neck squamous cell carcinoma (HNSCC) patient–derived xenograft models.

Options: View larger image (or click on image) Download as PowerPoint
Efficacy of evofosfamide alone or with radiotherapy in head and neck squ...
Evofosfamide (evo) was assessed as a single agent (50 mg/kg i.p. qd × 5 weekly for 3 cycles) or in combination with radiotherapy (RT, 1 × 10 Gy on day 5 of the first cycle) by growth delay in the laryngeal patient-derived xenograft (PDX) ACS-HN06 (A) and the lingual PDXs ACS-HN07 (B) and ACS-HN08 (C). The patient from whom ACS-HN06 was derived had received prior radiotherapy and high-dose cisplatin, whereas ACS-HN07 and ACS-HN08 were therapy-naive. Growth plots show the volume of the median tumor at each assessment. Survival analyses used the time to 4-fold increase in starting tumor volume (RTV4) as the experimental endpoint, with treatment effects assessed by log-rank test (evo vs. control vehicle [ctrl], evo + RT vs. RT alone). Cohort sizes were 7–10 per group. Representative H&E and pimonidazole (pimo) immunostains are shown for each model. Hypoxic fractions relative to the Hoechst 33258–positive (H33258-positive) tumor area are expressed as the mean ± SEM of whole sections from 4–7 tumors per model. The number of mitotic cells per 10 high-power fields was scored by a consultant pathologist (DK). Scale bars: 50 μm (H&E) and 500 μm (pimo). SCC, squamous cell carcinoma; HR, hazard ratio.