Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory KRAS G12C -Mutant NSCLC for Immune Checkpoint Blockade

To address RAS pathway hyperactivation and targeted therapy resistance in KRASG12C-mutant non-small cell lung cancer (NSCLC), we evaluated the potential of the RAS(ON) G12C-selective covalent inhibitor elironrasib and the RAS(ON) multi-selective inhibitor daraxonrasib combination to maximize RAS pathway suppression and forestall pathway reactivation in a series of preclinical models. We demonstrate that the RAS(ON) inhibitor doublet induces profound and sustained tumor regressions and overcomes the increased RAS pathway oncogenic flux that underlies resistance to inactive state-selective KRASG12C inhibitors in NSCLC. Additionally, in immune-competent preclinical models, the RAS(ON) inhibitor doublet enhances tumor immune recognition by boosting antigen presentation and remodeling the suppressive tumor microenvironment, thus promoting immune-dependent complete regressions and sensitization of an immunorefractory model to checkpoint blockade. Collectively, these findings provide a preclinical rationale for the evaluation of a targeted RAS(ON) inhibitor doublet therapy regimen in combination with immune checkpoint blockade (ICB) in patients with KRASG12C-mutant NSCLC. SIGNIFICANCE: The combination of a RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitor mitigates clinical resistance mechanisms to KRASG12C(OFF) inhibitors and enhances tumor immune recognition, overcoming ICB resistance. These preclinical findings highlight the potential for a RAS(ON) targeted therapy regimen in combination with anti-PD-(L)1 in patients with KRASG12C-mutant NSCLC. See related commentary by Molina-Arcas and Downward, p. 1044.