Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-refractory KRASG12C-mutant NSCLC for Immune Checkpoint Blockade

To address RAS pathway hyperactivation and targeted therapy resistance in KRASG12C-mutant 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 immuno-refractory 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 in patients with KRASG12C-mutant NSCLC. Overall design: Mice bearing NCI-H2122 subcutaneous xenograft tumors were treated with 7 consecutive daily doses of elironrasib at 100 mg/kg and daraxonrasib at 25 mg/kg as single agents or in combination. Tumors were harvested at 8 and 24 hours post the last dose (n = 3 per time point) for bulk RNA sequencing analysis. Mice bearing 3LL-?NRAS subcutaneous syngeneic tumors were treated for 8 consecutive daily doses of elironrasib at 30 mg/kg and daraxonrasib at 25 mg/kg as single agents or in combination. Tumors were harvested at 24 hours post the last dose (n = 5 per time point) for bulk RNA sequencing analysis