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
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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 7

Evofosfamide reduces nodal hypoxia and augments CTLA-4 blockade in head and neck squamous cell carcinoma (HNSCC) tumor models.

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Evofosfamide reduces nodal hypoxia and augments CTLA-4 blockade in head ...
(A) Experimental design for assessing target engagement (as a reduction in the CA9-positive hypoxic tumor cell fraction) in nodal lesions disseminated from an orthotopic UT-SCC-74B tumor model. (B) Definiens TissueStudio analysis of CA9 staining in nodal lesions from treated and control animals. The top row shows CA9 staining (red), pan-cytokeratin staining (green), and DAPI staining (blue) in representative sections from each treatment group. The middle row shows tissue segmentation into tumor (orange), normal tissue (blue), necrosis (green), and artifact (gray). The bottom row shows the cellular classification, in which individual cells (identified by DAPI staining) are assigned 1 of 4 categories according to CA9 expression: negative (white), low (yellow), medium (orange), or high (red). Scale bars: 200 μm. (C) Comparison of the proportion of viable tumor cells showing negative, low, medium, or high expression of CA9 in nodal lesions dissected from animals treated with control vehicle (n = 2), evofosfamide monotherapy (evo, n = 3), or evofosfamide plus image-guided radiotherapy (IGRT; comb, combination n = 3) was analyzed using machine learning in the Definiens TissueStudio environment. Statistical significance of the reduction in CA9 staining in treated tumor sections was assessed by χ2 test. (D) Efficacy of evofosfamide (50 mg/kg i.p. qd × 5 weekly for 2 cycles interspaced by 1-week treatment holiday) alone or with concurrent anti–CTLA-4 antibody (9H10, 100 μg/dose i.p. q3d × 3 weekly) in the syngeneic HNSCC model, SCC-7. The tumor growth plot (left panel) shows the mean ± SEM tumor volume for 10 animals per treatment group. Survival analysis (right panel) used log-rank tests with time to tumor volume ≥1,000 mm3 to define events. HR, hazard ratio.