Adagrasib

• Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models genomically characterized by KRAS-G12C and homozygous loss of CDKN2A
• Hydroxychloroquine prevents resistance and potentiates the antitumor effect of SHP2 inhibition in NF1-associated malignant peripheral nerve sheath tumors
• A real-world pharmacovigilance study of KRAS G12C mutation inhibitors based on the food and drug administration adverse event reporting system

Adagrasib (brand name Krazati) is an oral, small-molecule inhibitor that specifically targets KRAS G12C mutations, which are commonly found in certain cancers, including:

* Non-small cell lung cancer (NSCLC)

* Colorectal cancer

* Pancreatic cancer

* Mechanism of action:

Adagrasib irreversibly binds to the **KRAS G12C mutant protein**, locking it in its inactive state. This prevents the downstream signaling that promotes tumor growth.

* Approved indication:

As of late 2022, the FDA approved adagrasib for **NSCLC with KRAS G12C mutations** in patients who have received at least one prior systemic therapy.

* Combination therapy potential:

Adagrasib is being studied in **combination with other agents**, such as:

• Immune checkpoint inhibitors (e.g., pembrolizumab)
• EGFR inhibitors in colorectal cancer (e.g., cetuximab)
• SHR inhibitors or MEK inhibitors in preclinical models

Advantages over sotorasib (another KRAS G12C inhibitor):

Some studies suggest adagrasib may have better central nervous system penetration, offering hope for patients with brain metastases.

Adagrasib for Non-small cell lung cancer intracranial metastases