FDA Approval Announcement
On December 12, 2022, Mirati Therapeutics announced that the U.S. Food and Drug Administration (FDA) had granted accelerated approval to Krazati (adagrasib) for the treatment of adult patients with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC) who have received at least one prior systemic therapy.
This indication was approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.Krazati is the second targeted therapy approved by the FDA to directly inhibit mutant KRAS activity.
Overview of Krazati (adagrasib)
Krazati (adagrasib) is a highly selective and potent oral small-molecule KRAS inhibitor and a targeted treatment option for adult patients with KRAS mutations.
Basis for Approval: Phase 2 KRYSTAL-1 Study (NCT03785249)
Accelerated approval was based on data from the open-label registration-supporting cohort of the Phase 2 KRYSTAL-1 study, which evaluated adagrasib in 112 adult patients with NSCLC following prior systemic therapy.
Patients received 600 mg of adagrasib orally twice daily until disease progression or unacceptable toxicity.
Key Efficacy Results
Primary efficacy endpoints were ORR and DOR per RECIST 1.1, assessed by blinded independent central review:
Objective Response Rate (ORR): 43% (95% CI: 34–53)
Disease Control Rate: 80% (95% CI: 71–87)
Median Duration of Response (DOR): 8.5 months (95% CI: 6.2–13.8)
Safety Profile
Most common adverse reactions (≥ 20%):Diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.
Companion Diagnostics Approved
The FDA also approved two companion diagnostics for Krazati:
Qiagen therascreen KRAS RGQ PCR Kit (tissue)
Agilent Resolution ctDx FIRST Assay (plasma)
If no mutation is detected in a plasma specimen, tumor tissue testing should be performed.
Comparison with Prior KRAS Inhibitor
On May 29, 2021, the FDA granted accelerated approval to Lumakras (sotorasib, AMG 510) developed by Amgen for the treatment of patients with NSCLC harboring the KRAS G12C mutation.
The approval of Krazati (adagrasib) represents a positive advance for thousands of patients with KRAS G12C mutations, providing an additional effective therapeutic option.
