Preclinical combination approaches with the pan-KRAS inhibitor AMG 410 in KRAS- mutant cancers

KRAS is the most frequently mutated oncogene in solid tumors. Covalent KRAS G12C-selective inhibitors have been approved for G12C-mutant non-small cell lung cancer (NSCLC). Despite their clinical success, the durability of response and emergence of resistance have tempered the efficacy of KRAS-targeted therapies, leading to the exploration of combination strategies to enhance clinical outcomes. AMG 410, currently in Phase 1, is a reversible pan-KRAS inhibitor capable of targeting KRAS mutants (e.g., G12D, G12V, and G12C) and wild-type amplification. These altered KRAS alleles are prevalent in multiple solid tumor indications, particularly colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and NSCLC. Preclinically, AMG 410 demonstrated significant tumor growth inhibition as a single agent in multiple cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Guided by reverse translation findings from the G12C-selective inhibitor sotorasib, we evaluated AMG 410 combination approaches in preclinical models to proactively mitigate potential primary and acquired resistance mechanisms. A large panel of diverse KRAS -mutant cancer cell lines representing three indications (NSCLC, CRC, and PDAC) was screened in combination with inhibitors of the RAS signaling pathway, DNA damage repair pathways, cell cycle regulators, and select chemotherapy agents. Robust synergistic effects on cell viability were observed with pan-HER kinase and PI3K/mTOR inhibitors. To further explore resistance mechanisms, an AMG 410-anchored genome-wide CRISPR screen was performed. The Hippo pathway and YAP1 were identified as key modifiers of response to KRAS inhibition. Co-treatment with YAP/TEAD inhibitors demonstrated strong synergy in multiple KRAS -mutant cell lines. To assess whether these observations translated to improved efficacy in vivo, rational combinations were evaluated in tumor xenograft models. Consistent with the in vitro synergy observed with pan-HER inhibition, the combination of AMG 410 with panitumumab resulted in tumor regression in a CRC PDX model. Additionally, enhanced anti-tumor activity was observed when AMG 410 was combined with chemotherapy agents in CRC and PDAC xenografts. Building on the potential benefit of clinical KRAS G12C immune-oncology combinations, treatment with AMG 410 and PD-1 blockade in a KRAS G12D syngeneic CRC model led to tumor regression and significantly enhanced survival. Finally, co-treatment with a TEAD inhibitor enhanced durability of response to AMG 410 in vivo. Taken together, these findings support the clinical investigation of AMG 410 combination strategies to extend the therapeutic benefit of KRAS inhibition across diverse KRAS -mutant cancers.