adagrasib

Adagrasib, sold under the brand name Gavreto and previously known by the code MRTX-849, is a selective covalent inhibitor of KRAS G12C developed by Mirati Therapeutics for the treatment of cancer. It targets the KRAS G12C mutation by forming a covalent bond with the cysteine residue at position 12, locking KRAS in an inactive GDP-bound state and inhibiting downstream signaling through the MAPK pathway. The drug is taken orally.

In clinical development, adagrasib has been investigated in KRAS G12C–mutated cancers, with the most progressed program in non-small cell lung cancer (NSCLC). In trials involving patients who had received prior therapy, objective responses were observed, with reported response rates generally in the range of about 40–45% in NSCLC, and durability of response extending for several months. The drug has also been studied in colorectal and other KRAS G12C–mutant tumors, including assessments of activity in patients with brain metastases due to some CNS penetration. Ongoing studies are exploring adagrasib in combination regimens and in earlier lines of therapy across multiple tumor types.

Regulatory status: In December 2022, the U.S. Food and Drug Administration approved Gavreto for the treatment of adult patients with locally advanced or metastatic NSCLC harboring KRAS G12C mutation who have received at least one prior systemic therapy. The approval marked a separate targeted option in the expanding landscape of KRAS G12C inhibitors, alongside other agents in development.

Common adverse events reported in clinical studies include gastrointestinal symptoms such as diarrhea, nausea, and vomiting, as well as fatigue and liver enzyme elevations. Serious adverse events can occur and may include interstitial lung disease/pneumonitis and hepatotoxicity.