Abstract 5733: Combining KRASG12C(ON) inhibition with SHP2 and immune checkpoint blockade to enhance anti-tumor immunity and overcome development of resistance in lung cancer
Authors: Anastasiou Panayiotis , Tomaschko Mona , Boumelha Jesse , Rana Sareena , Moore Christopher , Molina-Arcas Miriam , Downward Julian 
Published: April 2023

Abstract
The recent approval of KRASG12C mutant-specific inhibitors has transformed the clinical practice of lung cancer patients harboring KRASG12C mutations. However, clinical data show that resistance develops rapidly after initial responses, suggesting that combination therapies will be needed. Ideally, these combinations should not only overcome adaptive or acquired resistance but also maintain or even enhance the positive immunomodulatory effects that KRASG12C inhibitors (G12Ci) have in the tumor microenvironment (TME). Most of the G12Ci being tested in clinical trials target GDP-bound KRAS (OFF state), which makes them vulnerable to upstream pathway reactivation. In this study we use a covalent tri-complex KRASG12C(ON) inhibitor, RM-029, which targets KRASG12C in the active state. Treatment with RM-029 still resulted in some degree of adaptive RAS pathway reactivation, which can be blocked using the SHP2 inhibitor RMC-4550. In vivo, this combination enhanced tumor regressions and improved overall survival in two different KRASG12C lung cancer models. In an immunogenic KRASG12C lung cancer model both KRASG12C(ON) and SHP2 inhibitors remodel the TME and are able to drive durable responses, which are enhanced when both compounds are combined. However, in this anti-PD1 sensitive model the combination of RM-029 with anti-PD1 generated more complete responses than the combination of RM-029 and RMC-4550. In an immune-excluded anti-PD1 resistant model, KRASG12C(ON) and SHP2 inhibitors also promoted a profound remodelling of the TME, with increased infiltration and activation of T cells accompanied by a reduction of tumor-promoting myeloid cells. Importantly, only the combination of both KRASG12C(ON) and SHP2 inhibitors sensitized these immune-excluded tumors to anti-PD1 blockade, resulting in durable responses and immune memory. Our preclinical results show that RM-029 as single agent or in combination with RMC-4550 and/or anti-PD1 can induce anti-tumor immunity and generate complete responses, especially in immunogenic models. To study if this immunological response could also target G12Ci-resistant subpopulations within the tumor, we used our immunogenic cell line (KPAR) to generate reporter-traced G12Ci sensitive (KPARG12C) and resistant (KPARG12D) cells that can be monitored over time via in vivo luciferase imaging and end point flow cytometry. We find evidence of bystander immune mediated killing of G12Ci-resistant cells in response to the different treatment combinations. Overall, our preclinical results demonstrate the potential of the combination of KRASG12C(ON) inhibitors with SHP2 and/or immune checkpoint blockade not only by targeting KRAS-driven proliferation in tumor cells but by stimulating anti-tumor immunity to target both G12Ci sensitive and resistant cells.
Citation Format: Panayiotis Anastasiou, Mona Tomaschko, Jesse Boumelha, Sareena Rana, Christopher Moore, Miriam Molina-Arcas, Julian Downward. Combining KRASG12C(ON) inhibition with SHP2 and immune checkpoint blockade to enhance anti-tumor immunity and overcome development of resistance in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5733.