Azvudine enhances durable tumor control with sotorasib in a CT26-mKRAS G12C syngeneic model Limin Jia [1] , Zhiyong Qin [1] , Pan Li* [1] ++...

https://www.academia.edu/2998-7741/3/3/10.20935/AcadOnco8419 Introduction: KRAS G12C inhibitors can rapidly suppress oncogenic proliferative signaling and achieve meaningful initial tumor control, but their clinical benefit is often limited by on-treatment regrowth and restricted durability of response. We investigated whether azvudine (FNC) could enhance the durability of sotorasib (AMG510) treatment in an immunocompetent syngeneic model. Materials and methods: FNC in combination with AMG510 was evaluated in CT26-mKRAS G12C tumor-bearing BALB/c mice, with anti-programmed cell death protein 1 (anti-PD-1) plus AMG510 included as a contextual benchmark. Antitumor activity was assessed by monitoring tumor growth over time, day 17 tumor volume, area under the tumor growth curve (AUC), complete response (CR) rate, and Kaplan–Meier survival analysis. Prespecified factorial analyses were performed to assess interaction effects in the vehicle/FNC/AMG510/FNC + AMG510 and vehicle/anti-PD-1/AMG510/anti-PD-1 + AMG510 subsets. Results: AMG510 monotherapy induced rapid initial tumor control, but tumor regrowth emerged during the dosing phase. In the vehicle/FNC/AMG510/FNC + AMG510 factorial subset, FNC + AMG510 showed significant interaction effects for day 17 tumor volume (p = 0.0022) and AUC from day 0 to day 17 (p = 0.0029), supporting a greater-than-additive combination effect under the present experimental conditions. FNC + AMG510 also improved durability-related outcomes, including delayed on-treatment tumor regrowth, an increased CR rate (5/10), and prolonged median survival to 66 days. Anti-PD-1 + AMG510 was included as a contextual immunotherapy-based reference arm and showed antitumor activity in a subset of animals, including 2/10 CRs and a median survival of 49 days, although no significant interaction was observed in the prespecified factorial analysis. Conclusions: FNC plus AMG510 improved the durability of tumor control and delayed renewed tumor growth following initial control in an immunocompetent CT26-mKRAS G12C syngeneic model. These findings support further investigation of FNC as a potential non- immune checkpoint inhibitor (ICI) combination partner for KRAS G12C inhibitor-based therapy. https://www.academia.edu/journals/academia-oncology/articles?source=journal-top-nav