Abstract B012: Effects of adagrasib on oncogenic signaling, immune cell regulation and biomarkers of response in preliminary clinical analyses

Abstract The recent approval of KRAS G12C inhibitors has provided novel treatment options for lung, colorectal and other cancer patients harboring this mutation and has changed the landscape of research for these cancers. Current priorities in the field include characterizing the mechanism of action of KRAS G12C inhibitors and the mechanisms underlying resistance to KRAS inhibition. Utilizing access to pre and post-treatment patient samples from KRYSTAL-1, preliminary gene expression analyses from baseline and post-adagrasib (Cycle 1, Day 8) treated patient samples demonstrated multiple oncogenic pathway gene signatures, including MYC, mTOR, cell cycle, EMT and inflammation-related signatures, were significantly regulated by adagrasib. KRAS/MAPK pathway and cell cycle-related genes including ETV4, CCND1, DUSP6, TOP1, and CENPA, as well as the Singh KRAS dependency signature were significantly downregulated in Cycle1, Day 8 compared to baseline tumor biopsies. Genes implicated in inflammation and the immune response were significantly upregulated in Cycle 1, Day 8 compared to baseline tumor biopsies. In agreement with the gene expression data as well as findings from syngeneic mouse models, preliminary immunohistochemical analysis on matched baseline, post-adagrasib treated (Cycle 1, Day 8), and end of treatment FFPE patient samples revealed marked changes in tumor cell mechanistic biomarkers and immune cell types following adagrasib treatment. These observations included decreased tumor Ki67 and increased tumor PD-L1, as well as marked alterations in tumor immune cell composition, including increased CD8+ T cells and decreased MDSCs following adagrasib treatment in several patients. Finally, flow cytometry and TCRb sequencing data from adagrasib and pembrolizumab-treated patient blood samples demonstrated an increase in several activated CD8+ T cell populations and the emergence of new T cell clones in a subset of patients after combination treatment. Together, these data suggest robust evaluation of patient biopsies pre and post adagrasib treatment may better predict outcomes that can be achieved in patients harboring KRASG12C mutant cancers and can guide early clinical development strategies, including support for combining adagrasib with immune checkpoint inhibitors. Citation Format: Jill Hallin, Laura Hover, Julio Fernandez-Benet, Adam Pavlicek, Kenna Anderes, Pasi A. Jänne, Gregory J. Riely, Alexander I. Spira, Jun Zhang, Peter Olson, James G. Christensen. Effects of adagrasib on oncogenic signaling, immune cell regulation and biomarkers of response in preliminary clinical analyses [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B012.