Background: KRAS mutations are common in pancreatic ductal adenocarcinoma (PDAC). While 90% of PDAC tumors display activating mutations in KRAS, only ̃2% are G12C, a specific KRAS mutation targeted by inhibitors such as sotorasib or adagrasib. MEK, which lies downstream of KRAS, is an attractive target to more broadly counteract elevated MAPK signaling regardless of the upstream mutation. However, FDA registered MEK inhibitors are prone to pathway reactivation events, which limit their utility in RAS mutant disease and necessitate chronic pathway inhibition that contributes to on-target toxicity. In contrast, IMM-1-104 is a novel, allosteric dual-MEK inhibitor designed to block pathway reactivation by disrupting phosphorylation of both MEK and ERK and has a short plasma drug half-life. These characteristics enable IMM-1-104 to drive deep cyclic MAPK pathway inhibition, with the potential to inhibit tumors driven by diverse RAS mutations. Methods: IMM-1-104 was tested head-to-head versus sotorasib, adagrasib, selumetinib and binimetinib in a series of preclinical models to characterize differential activity of each compound against tumors driven by diverse KRAS mutations. Cell-based 2D biochemical and 3D growth assays were performed across nine PDAC models, and the Capan-2 PDAC xenograft animal model was used to evaluate single agent activity of IMM-1-104 (75, 100, 150 mg/kg BID p.o. or 150 mg/kg QD p.o.) vs. sotorasib or adagrasib (30 and 100 mg/kg QD p.o. each) for 21 days treatment after tumors had reached volumes of 150 to 200 mm3. Results: IMM-1-104 alone led to reductions in both pERK and pMEK across all 9 PDAC models tested (KRAS status shown), including Hs766T (Q61H), MIA PaCa-2 (G12C), Capan-2 (G12V), AsPC-1 (G12D), CFPAC-1 (G12V), BxPC3 (wild type), Panc 10.05 (G12D), Capan-1 (G12V) and PSN1 (G12R). A head-to-head comparison in vivo demonstrated no Tumor Growth Inhibition (TGI) by sotorasib and adagrasib in KRAS-G12V mutant Capan-2 PDAC tumors, while IMM-1-104 prompted TGIs of 49 to 84% across all doses and schedules tested. Conclusions: Despite multiple clinical studies, including Phase 2 studies for the MEK inhibitors trametinib and selumetinib, limited progress has been made in PDAC treatment since FOLFIRINOX’s approval in 2011. The Phase 2 KRYSTAL-1 and Phase 1/2 CodeBreaK 100 studies recently reported promising activity in KRAS-G12C PDAC, suggesting an opportunity for disruption of KRAS addiction. IMM-1-104 and sotorasib previously demonstrated comparable tumor regressions in vivo in a KRAS G12C mutant model, MIA PaCa-2 (2021 EORTC). Examining the broader activity of IMM-1-104 across 9 PDAC tumor models yielded data suggesting that deep, cyclic MEK inhibition by IMM-1-104 has the potential to offer a unique advantage over first generation MEK inhibitors and KRAS-G12C inhibitors in PDAC by inhibiting tumors driven by a broader range of more common KRAS mutations.