Utilizing Adagrasib as Treatment of KRAS G12C-Mutated GI Malignancies

Tanios S. Bekaii-Saab, MD, FACP, medical oncologist, medical director, Cancer Clinical Research Office, vice chair and section chief, Medical Oncology, Department of Internal Medicine, Mayo Clinic, discusses the differences between adagrasib (MRTX849) and other KRAS inhibitors.

Research in targeting KRAS mutation is fairly recent as for a long time, no agents were available besides MEK inhibitors which could indirectly affect the mitogen-activated protein kinase pathway downstream. The 2 agents that made it to first being tested, targeting KRAS, specifically KRAS G12C, are sotorasib (Lumakras) and adagrasib.

Adagrasib is an investigational and highly selective oral, small-molecule inhibitor which is currently being examined for the treatment of patients harboring the KRAS G12C mutation. The agent has a long half-life, targets KRAS G12C, enables the inhibition of KRAS dependent signaling for the complete dose interval, and maximizes the depth and duration of human activity.

Transcription:

0:08 | It is difficult to compare different agents. When you think about the KRAS protein, the KRAS protein cycles between guanine triphosphate on and guanosine diphosphate [GDP] off, and it cycles every 24 hours. Adagrasib covalently binds to KRAS G12C. It is an irreversible inhibitor, so it sticks to it, and you cannot just get it off. It selectively binds KRAS G12C to its inactive GDP and keeps it in the inactive state.

0:58 | Now, the next thing about adagrasib is that it's optimized for the desired properties of the KRAS G12C inhibitor. You need a longer half-life and its recycling takes about 24 hours. It sticks around through the lifetime of this resynthesis. It has those dependent decays so we understand, predictably, how the dose relates to pharmacokinetics.

1:34 | Although it's not as relevant for my practice, for the brain cancer practice, it actually does have central nervous system penetration. It goes through the blood brain barrier. With adagrasib, because of its long half-life and how it targets KRAS G12C, it enables the inhibition of KRAS dependent signaling for the complete dose interval. When you think about adagrasib and how it works, it maximizes the depth and duration of an entire human activity. I think it is pretty successful in terms of showing a variety of cancers so far.