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

doi:10.1172/jci.insight.122204

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. GrénmanLaura 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

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

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.

Original language	English (US)
Article number	e122204
Journal	JCI Insight
Volume	3
Issue number	16
DOIs	https://doi.org/10.1172/jci.insight.122204
State	Published - Aug 23 2018
Externally published	Yes

Keywords

Cancer
Head & neck cancer
Oncology
Therapeutics
hypoxia

ASJC Scopus subject areas

General Medicine

Access to Document

10.1172/jci.insight.122204

Cite this

Jamieson, S. M. F., Tsai, P., Kondratyev, M. K., Budhani, P., Liu, A., Senzer, N. N., Gabriela Chiorean, E., Jalal, S. I., Nemunaitis, J. J., Kee, D., Shome, A., Wong, W. W., Li, D., Poonawala-Lohani, N., Kakadia, P. M., Knowlton, N. S., Lynch, C. R. H., Hong, C. R., Lee, T. W., ... Hunter, F. W. (2018). Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma. JCI Insight, 3(16), Article e122204. https://doi.org/10.1172/jci.insight.122204

Jamieson, SMF, Tsai, P, Kondratyev, MK, Budhani, P, Liu, A, Senzer, NN, Gabriela Chiorean, E, Jalal, SI, Nemunaitis, JJ, Kee, D, Shome, A, Wong, WW, Li, D, Poonawala-Lohani, N, Kakadia, PM, Knowlton, NS, Lynch, CRH, Hong, CR, Lee, TW, Grénman, RA, Caporiccio, L, McKee, TD, Zaidi, M, Butt, S, Macann, AMJ, McIvor, NP, Chaplin, JM, Hicks, KO, Bohlander, SK, Wouters, BG, Hart, CP, Print, CG, Wilson, WR, Curran, MA & Hunter, FW 2018, 'Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma', JCI Insight, vol. 3, no. 16, e122204. https://doi.org/10.1172/jci.insight.122204

@article{0712dafed1e3449a97f93c13710d0c96,

title = "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.",

keywords = "Cancer, Head & neck cancer, Oncology, Therapeutics, hypoxia",

author = "Jamieson, {Stephen M.F.} and Peter Tsai and Kondratyev, {Maria K.} and Pratha Budhani and Arthur Liu and Senzer, {Neil N.} and {Gabriela Chiorean}, E. and Jalal, {Shadia I.} and Nemunaitis, {John J.} and Dennis Kee and Avik Shome and Wong, {Way W.} and Dan Li and Nooriyah Poonawala-Lohani and Kakadia, {Purvi M.} and Knowlton, {Nicholas S.} and Lynch, {Courtney R.H.} and Hong, {Cho R.} and Lee, {Tet Woo} and Gr{\'e}nman, {Reidar A.} and Laura Caporiccio and McKee, {Trevor D.} and Mark Zaidi and Sehrish Butt and Macann, {Andrew M.J.} and McIvor, {Nicholas P.} and Chaplin, {John M.} and Hicks, {Kevin O.} and Bohlander, {Stefan K.} and Wouters, {Bradly G.} and Hart, {Charles P.} and Print, {Cristin G.} and Wilson, {William R.} and Curran, {Michael A.} and Hunter, {Francis W.}",

year = "2018",

month = aug,

day = "23",

doi = "10.1172/jci.insight.122204",

language = "English (US)",

volume = "3",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "16",

}

TY - JOUR

T1 - Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma

AU - Jamieson, Stephen M.F.

AU - Tsai, Peter

AU - Kondratyev, Maria K.

AU - Budhani, Pratha

AU - Liu, Arthur

AU - Senzer, Neil N.

AU - Gabriela Chiorean, E.

AU - Jalal, Shadia I.

AU - Nemunaitis, John J.

AU - Kee, Dennis

AU - Shome, Avik

AU - Wong, Way W.

AU - Li, Dan

AU - Poonawala-Lohani, Nooriyah

AU - Kakadia, Purvi M.

AU - Knowlton, Nicholas S.

AU - Lynch, Courtney R.H.

AU - Hong, Cho R.

AU - Lee, Tet Woo

AU - Grénman, Reidar A.

AU - Caporiccio, Laura

AU - McKee, Trevor D.

AU - Zaidi, Mark

AU - Butt, Sehrish

AU - Macann, Andrew M.J.

AU - McIvor, Nicholas P.

AU - Chaplin, John M.

AU - Hicks, Kevin O.

AU - Bohlander, Stefan K.

AU - Wouters, Bradly G.

AU - Hart, Charles P.

AU - Print, Cristin G.

AU - Wilson, William R.

AU - Curran, Michael A.

AU - Hunter, Francis W.

PY - 2018/8/23

Y1 - 2018/8/23

N2 - 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.

AB - 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.

KW - Cancer

KW - Head & neck cancer

KW - Oncology

KW - Therapeutics

KW - hypoxia

UR - http://www.scopus.com/inward/record.url?scp=85062249490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062249490&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.122204

DO - 10.1172/jci.insight.122204

M3 - Article

C2 - 30135316

AN - SCOPUS:85062249490

SN - 2379-3708

VL - 3

JO - JCI Insight

JF - JCI Insight

IS - 16

M1 - e122204

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this