Adagrasib (MRTX849) is an oral, small-molecule KRAS inhibitor developed by Mirati Therapeutics. KRAS mutations are highly common in cancer and account for approximately 85% of all RAS family mutations.[A254941] However, the development of KRAS inhibitors has been challenging due to their high affinity for guanosine triphosphate (GTP) and guanosine diphosphate (GDP), as well as the lack of a clear binding pocket.[A187559] Adagrasib targets KRAS<sup>G12C</sup>, one of the most common KRAS mutations, at the cysteine 12 residue and inhibits KRAS-dependent signalling.[A254052] In a phase I/IB clinical study that included patients with KRAS<sup>G12C</sup>-mutated advanced solid tumors (NCT03785249), adagrasib exhibited anti-tumor activity. The phase II of the same study showed that in patients with KRAS<sup>G12C</sup>-mutated non-small-cell lung cancer (NSCLC), adagrasib was efficient without new safety signals.[A254052,A254057,A254946] In February 2022, the FDA accepted a new drug application (NDA) for adagrasib for the treatment of patients with previously treated KRAS<sup>G12C</sup>–positive NSCLC.[L43847] In December 2022, the FDA granted accelerated approval to adagrasib for the treatment of KRAS<sup>G12C</sup>-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.[L44361,L44366] Adagrasib joins [sotorasib] as another KRAS<sup>G12C</sup> inhibitor approved by the FDA.[A254062]
Adagrasib is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.[L44361] It is also indicated to treat KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) in combination with [cetuximab] in adults who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.[L51269] These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Their continued approval may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).
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