Abstract ND11: AZD0022: a potent, oral KRASG12D-selective inhibitor that drives robust pathway inhibition and anti-tumour activity in KRASG12D models

Abstract The small GTPase KRAS is frequently mutated in cancer and KRASG12D is its most common mutation, with ∼34% incidence in pancreatic ductal adenocarcinoma (PDAC), ∼12% in colorectal cancer (CRC) and ∼4% in non-small cell lung cancer (NSCLC). KRASG12D mutations disrupt the GTPase activity of the protein, resulting in elevated cellular levels of active, GTP-bound KRASG12D. KRASG12D mutations are therefore associated with increased and deregulated RAS signalling, driving uncontrolled cell proliferation and survival. Despite major advances in RAS-targeting in recent years, KRASG12D-cancers continue to represent an unmet medical need. AZD0022 is a potent, orally bioavailable, KRASG12D-selective reversible inhibitor with the potential to provide therapeutic benefit to patients with KRASG12D-mutated cancers. AZD0022 shows high affinity to both the active (KRASG12D-GTP) and inactive forms of KRASG12D (KRASG12D-GDP) protein by Surface Plasmon Resonance, and selectivity over wild-type KRAS. AZD0022 treatment drives robust and concentration-dependent biomarker inhibition in KRASG12D CRC, PDAC and NSCLC models in vitro and in vivo and inhibits proliferation and viability of KRASG12D-tumour cells across these indications. Following oral administration in mouse, rat and dog, AZD0022 exhibited significant oral exposure and long terminal elimination phase half-life values. Oral, chronic daily treatment of a panel of CRC, PDAC and NSCLC CDX (cell line-derived xenograft) and PDX (patient-derived xenograft) models with AZD0022 demonstrated broad anti-tumour activity of AZD0022 across KRASG12D-mutant tumour types. The therapeutic responses of KRASG12D CRC and PDAC models to AZD0022 were further improved by cetuximab combination treatment, with sustained regressions observed in both tumour types. Together, the pre-clinical pharmacology of AZD0022 supports its oral anti-tumor activity and KRASG12D-selectivity and shows that it has the potential to improve outcomes for patients with KRASG12D mutated cancers, either as monotherapy or in combination with other agents. AZD0022 is currently being investigated in the ALAFOSS-01 (NCT06599502) study, a first-in-human, open-label, multicenter, phase 1/2a study of AZD0022 in patients with KRASG12D-mutated solid tumors. Citation Format: Carla P. Martins, Alex Koers, Sreyoshi Mitra, Alison Peter, Katie Young, Christopher Chambers, Zoe Underwood, Kevin Beaumont, Sofia Guzzetti, Christopher Stubbs, Derek Barratt, Benjamin Phillips, Eleanor Wigmore, Melissa Chapman, Michele Moschetta, Simon Barry, Susan Critchlow, Michael Niedbala. AZD0022: a potent, oral KRASG12D-selective inhibitor that drives robust pathway inhibition and anti-tumour activity in KRASG12D models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr ND11.