The first KRAS inhibitor received accelerated approval, non-pharmacological targets, counterattack multiple drugs on the road

On May 28, 2021, the FDA announced the accelerated approval of the KRAS inhibitor Lumakras (sotorasib, AMG510) [1] for the treatment of non-small cell lung cancer (NSCLC) patients with KRAS G12C mutations.

KRAS gene carcinogenic mechanism

RAS (KRAS, NRAS, and HRAS) are the most commonly mutated gene families in cancer.

The RAS protein itself is a signal protein with GTPase activity.

Lumakras breaks through non-drugable targets

Although the carcinogenic principle of KRAS has been elucidated for a long time, no KRAS targeted drug has been available for more than 30 years before Lumakras.

In the crystallographic study of the complex that the compound binds to the KRAS G12C mutant, it was discovered that there is a "pocket" on the KRAS G12C mutant protein that can bind to small molecule drugs.

Lumakras is a drug developed based on the carcinogenic mechanism of KRAS.

Lumakras clinical efficacy

This approval is based on data from a study called CodeBreak 100.

A variety of drugs show clinical efficacy

The once non-medicinal target ushered in a counterattack.

MRTX849

MRTX849 is a small molecule inhibitor against KRAS G12C mutation.

The KRYSTAL-1 study is a multi-cohort phase I/II clinical study that included patients with KRAS G12C mutant NSCLC, patients with colorectal cancer (CRC), and patients with other solid tumors.

ELCC 2021 released data on the NSCLC cohort.

VS-6766

VS-6766 is a RAF/MEK inhibitor.

BGB-283

BGB-283 is a new type of RAF inhibitor that exists in a unique dimer form and can also inhibit the activity of EGFR.

In 2020, a phase I dose escalation/dose extension study published in the Journal of Clinical Oncology for the first time in humans evaluated BGB-283 in patients with solid tumors with B-RAF or K-RAS/N-RAS mutations The safety, tolerability and efficacy of the product.

The results of the study show that the maximum tolerated dose of BGB-283 is 40 mg/d.

In summary, whether it is Lumakras, which has been approved, or MRTX849, which has shown very good clinical effects, after many years, the target of unpreparable medicine has finally ushered in a breakthrough, which will bring good news to cancer patients around the world.

reference:

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K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions, doi:10.
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AMG 510 Shows Activity beyond NSCLC.
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KRYSTAL-1: Activity and preliminary pharmacodynamic analysis of adagrasib (MRTX849) in patients with advanced non-small-cell lung cancer(NSCLC) harboring KRASG12Cmutation.

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