Avasopasem Manganese Protects Against Radiation Induced Oral Mucositis and Enhances the Response of Squamous Cell Carcinoma of the Head and Neck to Ionizing Radiation and Radioimmune Therapy

Abstract

Locoregional recurrence (LRR) is the major cause of morbidity and mortality in patients with squamous cell carcinoma of the head and neck (HNSCC). For those patients that experience surgically unresectable LRR, median overall survival (OS) is less than one year. Approaches utilizing stereotactic ablative radiotherapy (SabR) and immuno-oncology agents such as Nivolumab (α-PD-1 inhibitor) in the salvage setting have become alternatives to conventional chemoradiation therapy. Despite improvements in OS, rates of acute oral mucositis (OM) and late toxicities (skin fibrosis) remain concerns with SabR in the context of re-irradiation. Here we present pre-clinical evidence that avasopasem manganese (GC4419), a highly selective superoxide dismutase mimetic that has received FDA Breakthrough Therapy Designation and is currently in a Phase III trial for reducing severe OM in patients undergoing chemoradiotherapy for locally advanced HNSCC (NCT03689712) also enhances the anti-tumor radiation response of HNSCC tumors. We demonstrate in pre-clinical animal models that avasopasem protects the normal mucosa of the mouse tongue from primary irradiation toxicity. We will also report the results of ongoing studies examining whether avasopasem protects murine mucosa from reirradiation as with SabR as a salvage therapy. Utilizing clonogenic survival assays, we demonstrate that avasopasem at physiologically achievable concentrations exhibits single agent anti-cancer activity and also enhances the response of HNSCC lines to irradiation. In tumor growth delay (TGD) experiments utilizing the syngeneic HNSCC tumor model, AT-84, when avasopasem is delivered in combination with biologically equivalent fractionation schedules of 17 Gy x 1 fxn, 10.24 Gy x 2 fxn, or 5 Gy x 5 fxn, an enhancement of the radiation response is achieved. This potentiation of the anti-tumor response with GC4419 is more pronounced at fraction doses exceeding the threshold considered for intensity modulated radiation therapy. In addition, when avasopasem is combined with radiation and an α-PD-1 inhibitor, a further enhancement of the radiation response is observed, indicating that it compliments radiotherapy combined with immunotherapy. The pre-clinical data strongly suggest that avasopasem should be combined with radio-immune therapy to not only enhance local tumor control, but also to provide normal tissue protection with SabR which may allow dose escalation and further improve treatment outcomes. Whether radiation combined with avasopasem and checkpoint inhibitor has an effect on metastasis is under examination.