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.

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“…Re-normalizing the oxygen tension of the tumor microenvironment represents an attractive modality to improve the efficacy of various therapies, especially immunotherapy. Low-dose VEGF inhibitors may improve the quality of the tumor vasculature (32), elimination of hypoxic tumor cells can potentially improve response to checkpoint blockade (33), and respiratory hyperoxia can re-oxygenate the environment and improve response to immunotherapy (34). At our institution, we recently opened a phase I/II randomized clinical trial of pembrolizumab versus pembrolizumab plus the type II diabetes drug metformin (which inhibits mitochondrial complex I, of which Ndufs4 is a subunit) in patients with advanced unresectable melanoma (NCT03311308), based on our preclinical work showing that metformin treatment can reduce tumor hypoxia and synergize with PD-1 blockade (16).…”

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

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