Abstract B073: Rational combination strategies enhance the depth and durability of zoldonrasib antitumor response in preclinical models of KRAS G12D pancreatic cancer

Abstract

KRAS G12D is the most common RAS variant in pancreatic ductal adenocarcinoma (PDAC) and a key oncogenic driver that elevates the levels of active, GTP-bound RAS (RAS(ON)). Zoldonrasib is an investigational RAS(ON) G12D-selective covalent tri-complex inhibitor that has demonstrated deep and durable antitumor activity across preclinical models of KRAS G12D cancers, including PDAC. However, as observed with other targeted therapies, adaptive and acquired resistance may limit the benefit of zoldonrasib as a monotherapy. Here we demonstrate that rational combination strategies of zoldonrasib with mechanistically distinct agents can enhance antitumor activity relative to the respective monotherapies, and potentially delay emergence of resistance to RAS(ON) inhibition in preclinical models of KRAS G12D PDAC. In-pathway combination of zoldonrasib with the RAS(ON) multi-selective inhibitor daraxonrasib achieved deeper RAS pathway suppression than either agent alone and drove deeper and more durable antitumor response in allograft models of KRAS G12D PDAC in vivo. Furthermore, the RAS(ON) inhibitor doublet forestalled resistance in a xenograft model of KRAS G12D PDAC. Combination of zoldonrasib with standard-of-care (SoC) chemotherapy, including gemcitabine/nab-paclitaxel (GnP) or FOLFIRINOX, further enhanced the depth and/or durability of antitumor responses relative to either monotherapy regimen in xenograft models of human KRAS G12D PDAC. Combination benefit was observed with both chemotherapy regimens, and moreover antitumor activity was maintained in a chemotherapy-resistant PDAC model. Additional novel combination strategies are being pursued to enhance the therapeutic potential of zoldonrasib. Collectively, these findings demonstrate that rational in-pathway and out-of-pathway combination strategies, including SoC chemotherapy, further enhance the depth and durability of zoldonrasib antitumor activity in preclinical models of KRAS G12D PDAC and provide strong preclinical rationale for the ongoing clinical evaluation of zoldonrasib in combination with daraxonrasib (RASolute 309) or chemotherapy (RASolute 305) in patients with KRAS G12D-mutant PDAC.