AMG 410 / Amgen - LARVOL DELTA

AMG 410: An H/NRAS-sparing pan-KRAS inhibitor with dual GTP(on)/GDP(off)-state activity for the treatment of diverse KRAS-mutant tumors (AACR 2025) - "Approved inhibitors (sotorasib & adagrasib) are only effective for tumors harboring the KRAS G12C mutation, however, and major unmet need remains for the larger population of patients (~140k patients/year, USA) that bear other oncogenic KRAS mutations (e.g., KRAS G12D, G12V, etc.).Leveraging insights from KRAS G12Ci, we here report the structure- and property-based design of a non-covalent "pan-KRAS" inhibitor, AMG 410, which binds to the most clinically relevant KRAS mutants (e.g., G12D, G12V, G13D; IC50 values = 1-4 nM) via the same allosteric pocket employed by approved KRAS G12C inhibitors. AMG 410 demonstrates strong pre-clinical efficacy, robustly lowing phosphorylated ERK levels throughout dosing cycles and achieving tumor stasis or regression across a broad set of colorectal, pancreatic, and lung cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models harboring a diverse set of KRAS mutant alleles including G12D, G12V,..."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • KRAS • NRAS