Discovery of AMG 510, a First in Class Oral KRAS G12C Inhibitor

Preclinical evidence and anti-tumour activity in the first dosing cohorts in patients with KRAS G12C mutated cancer

KRAS G12C is present in approximately 13% of lung adenocarcinoma, 3% of colorectal cancer and 2% of other solid tumours. The KRAS G12C mutant has a cysteine residue that has been exploited to design covalent inhibitors with promising preclinical activity. The research efforts have led to the discovery of AMG 510, the first KRAS G12C inhibitor in clinical development. On 30 October 2019, the investigators published in the Nature an article about itspreclinical evidence and furthermore, reported that in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts. 

KRAS is the most frequently mutated oncogene in cancer. The KRAS oncoprotein is a GTPase and an essential mediator of intracellular signalling pathways that are involved in tumour cell growth and survival. GTP binding to KRAS promotes binding of effectors to trigger signal transduction pathways including the RAF–MEK–ERK (MAPK) pathway. Somatic, activating mutations in KRAS prevent the association of GTPase-activating proteins, thus stabilizing effector binding and enhancing KRAS signalling.

Although there are clinically approved inhibitors of MEK, BRAF and EGFR for a subset of tumour types, to date there have been no clinical molecules that are selective for KRAS-mutated tumours, the authors wrote in the study background. Moreover, several MAPK pathway targeted therapies lack clinical efficacy for treatment of KRAS-mutated tumours. Additionally, non-tumour or non-mutant selective therapies can introduce on-target toxicities due to the inhibition of MAPK signalling in normal cells. This might limit the ability to combine such agents with standard of care treatments or immunotherapy.

The KRAS G12C mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity. The study team identified a series of novel acrylamide-based molecules that utilize a previously unexploited surface groove in KRAS G12C to substantially enhance potency and selectivity.

Intensive electrophile screening and structure-based design culminated in the discovery of AMG 510, the first KRAS G12C inhibitor to reach clinical testing in humans.

In the Nature paper, the authors presented the data on preclinical activity of AMG 510, its ability to induce tumour cell killing as monotherapy or when combined with other therapies, and the marked impact of AMG 510 on immune cell infiltration, which renders the tumour microenvironment highly sensitive to immunotherapy. They also presented promising evidence for clinical efficacy.

In particular, in preclinical analyses, treatment with AMG 510 led to the regression of KRAS G12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS G12D tumours, which suggests adaptive immunity against shared antigens.

Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts. The authors concluded that AMG 510 represents a potentially transformative therapy for patients for whom effective treatments are lacking.

 

Reference

Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature; Published online 30 October 2019. DOI: https://doi.org/10.1038/s41586-019-1694-1