Data from The KRAS^G12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy

• DOI: 10.1158/1535-7163.c.6543400.v1
• Publication Date: 2023-04-03T23:24:04Z
• Authors: David M. Briere; Shuai Li; Andrew Calinisan; Niranjan Sudhakar; Ruth Aranda; Lauren Hargis; David H. Peng; Jiehui Deng; Lars D. Engstrom; Jill Hallin; Sole Gatto; Julio Fernandez-B...; Adam Pavlicek; Kwok-Kin Wong; James G. Christensen; Peter Olson

<div>Abstract<p>KRAS<sup>G12C</sup> inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non–small cell lung cancer (NSCLC). PD-1 inhibitors approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) needed. <i>KRAS<sup>G12C</sup></i> mutations smoking-associated transversion associated with high tumor mutation burden, PD-L1 positivity, and an immunosuppressive microenvironment. To evaluate the potential of MRTX849 augment CIT, its impact on immune signaling response CIT was evaluated. In human xenograft models, increased MHC class I protein expression decreased RNA and/or plasma levels factors. a <i>Kras<sup>G12C</sup></i>-mutant CT26 syngeneic mouse model, intratumoral myeloid-derived suppressor cells M1-polarized macrophages, dendritic cells, CD4<sup>+</sup>, CD8<sup>+</sup> T cells. Similar results were observed genetically engineered (GEM) model. <i>Kras<sup>G12C</sup></i> demonstrated marked regression when tumors established immune-competent BALB/c mice; effect diminished grown T-cell–deficient <i>nu</i>/<i>nu</i> mice. Tumors progressed following anti–PD-1 or single-agent combination durable, complete responses (CRs). did not reestablish same mice that exhibited durable CRs rechallenged inoculum, demonstrating these developed adaptive antitumor immunity. GEM plus led progression-free survival compared either single agent alone. These data demonstrate KRAS inhibition reverses microenvironment sensitizes through multiple mechanisms.</p></div>