Abstract 6284: GC4419 protects again radiation induced oral mucositis, enhances the response of squamous cell carcinoma of the head and neck tumors to ionizing radiation, and enhances radioimmune therapy

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 immune oncology agents such as Nivolumab (α-PD-1 agonist) 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 a concern with SAbR, particularly in the context of re-irradiation. Here we present pre-clinical evidence that GC4419 (Galera Therapeutics), a highly selective superoxide dismutase mimetic that recently received FDA Breakthrough therapy status following a Phase II, randomized, placebo controlled trial for reducing the duration and incidence of severe OM in patients undergoing chemoradiation therapy for locally advanced HNSCC (NCT02508389) also enhances the anti-tumor radiation response of HNSCC tumors to irradiation. We demonstrate in pre-clinical animal models that GC4419 protects the normal mucosa of the mouse tongue from radiation exposure. Utilizing clonogenic survival assays, GC4419 demonstrates single agent anti-cancer activity at physiologically achievable concentrations, while also enhancing the response of HNSCC lines to irradiation. In tumor growth delay (TGD) experiments utilizing the syngeneic HNSCC tumor model, AT-84, when GC4419 is delivered 30-60 minutes pre-irradiation 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. In tumor cure rate (TCD50) studies, GC4419 enhanced radiation exposure with a DEF of 1.25. Furthermore, when GC4419 is combined with radiation and an α-PD-1 inhibitor, a further enhancement of the radiation response is observed, indicating that GC4419 compliments radiotherapy combined with immune oncology. We will also report the results of ongoing studies examining the potency of GC4419 in protecting normal murine mucosa in the setting of reirradiation relevant to SAbR as a salvage therapy. This potentiation of the anti-tumor response with GC4419 is more pronounced at doses exceeding the threshold to be considered for intensity modulated radiation therapy (IMRT). The accompanying pre-clinical data strongly suggest that GC4419 should be combined with radio-immune therapy to not only enhance local tumor control, but that the potential for normal tissue protection with SAbR also creates the opportunity for dose escalation and may further improvement in treatment outcome. Citation Format: Brock James Sishc, Elizabeth Polsdofer, Debabrata Saha, Michael Story. GC4419 protects again radiation induced oral mucositis, enhances the response of squamous cell carcinoma of the head and neck tumors to ionizing radiation, and enhances radioimmune therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6284.