Amgen has announced the development of AMG 410, a novel pan-KRAS inhibitor designed to address a significant gap in cancer treatment for patients with KRAS-mutant tumors. The investigational drug represents a potential breakthrough for the approximately 140,000 patients per year in the United States who harbor oncogenic KRAS mutations other than G12C.
Addressing Unmet Medical Need
Currently approved KRAS inhibitors, including sotorasib and adagrasib, are only effective for tumors harboring the KRAS G12C mutation. This limitation leaves a substantial patient population without targeted treatment options, as many patients bear other oncogenic KRAS mutations such as G12D and G12V.
AMG 410 was developed through structure- and property-based design, leveraging insights from KRAS G12C inhibitors. The non-covalent inhibitor binds to the most clinically relevant KRAS mutants via the same allosteric pocket employed by approved KRAS G12C inhibitors.
Potent Binding Activity
The investigational drug demonstrates strong binding affinity across multiple KRAS variants. AMG 410 shows potent activity against G12D, G12V, and G13D mutations with IC50 values ranging from 1-4 nM. This broad spectrum of activity positions the drug as a potential pan-KRAS solution for diverse tumor types.
Preclinical Efficacy Results
AMG 410 has demonstrated strong preclinical efficacy across multiple cancer models. The drug robustly lowers phosphorylated ERK levels throughout dosing cycles, indicating effective pathway inhibition. In xenograft studies, AMG 410 achieved tumor stasis or regression across a broad set of colorectal, pancreatic, and lung cancer models.
The preclinical testing included both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models harboring diverse KRAS mutant alleles including G12D and G12V. These results suggest the potential for clinical activity across multiple tumor types and KRAS mutation variants.
Dual-State Activity
AMG 410 exhibits dual GTP(on)/GDP(off)-state activity, representing an advancement in KRAS inhibitor design. This mechanism allows the drug to target KRAS in both its active and inactive conformations, potentially providing more comprehensive pathway inhibition compared to existing therapies.
The H/NRAS-sparing design of AMG 410 may also offer advantages in terms of selectivity and potential side effect profile, though clinical data will be needed to confirm these theoretical benefits.
Clinical Development Outlook
The development of AMG 410 represents Amgen's effort to expand treatment options for KRAS-mutant cancers beyond the currently addressable G12C population. The preclinical data across colorectal, pancreatic, and lung cancer models suggests potential broad applicability across multiple solid tumor types.
The findings were presented at AACR 2025, highlighting the continued industry focus on developing next-generation KRAS inhibitors to address the substantial unmet medical need in this patient population.
