AMG 410 / Amgen - LARVOL DELTA

Discovery of AMG 410, a potent, orally bioavailable pan-KRAS inhibitor (ACS-Fall 2025) - "While such inhibitors proved well-tolerated and orally efficacious in KRAS G12D and G12V xenograft models, they demonstrated pharmacokinetic limitations that rendered them unattractive for clinical development. Here, we describe the optimization of such early inhibitors to provide AMG 410, a potent, oral pan-KRAS inhibitor, which demonstrates suitable pharmacokinetic and pharmacodynamic properties to support clinical development."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer • Solid Tumor • HRAS • KRAS • NRAS

AMG 410 Alone and in Combination With Other Agents in Participants With KRAS Altered Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=434 | Not yet recruiting | Sponsor: Amgen

New P1 trial • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor

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