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FDA: accelerated approval to Krazati for KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer

The Food and Drug Administration ( FDA ) has granted accelerated approval to Krazati ( Adagrasib ), a RAS GTPase family inhibitor, for 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.

FDA has also approved the QIAGEN therascreen KRAS RGQ PCR kit (tissue) and the Agilent Resolution ctDx FIRST Assay ( plasma ) as companion diagnostics for Krazati. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

Approval was based on KRYSTAL-1, a multicenter, single-arm, open-label clinical trial which has included patients with locally advanced or metastatic NSCLC with KRAS G12C mutations.
Efficacy was evaluated in 112 patients whose disease has progressed on or after Platinum-based chemotherapy and an immune checkpoint inhibitor, given either concurrently or sequentially. Patients received Adagrasib 600 mg orally twice daily until disease progression or unacceptable toxicity.

The main efficacy outcome measures were confirmed objective response rate ( ORR ) according to RECIST 1.1, as evaluated by blinded independent central review, and duration of response ( DOR ).
The ORR was 43% ( 95% CI: 34%, 53% ) and median DOR was 8.5 months ( 95% CI: 6.2, 13.8 ).

The most common adverse reactions ( 20% or more ) were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.
The most common laboratory abnormalities ( 25% or more ) were decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.

The recommended Adagrasib tablet dose is 600 mg orally twice daily until disease progression or unacceptable toxicity. ( Xagena )

Source: FDA, 2022