On December 12, 2022, the FDA accelerated the approval of adagrasib (Krazati; Mirati Therapeutics), a RAS GTPase inhibitor, for adults with locally advanced or metastatic non–small-cell lung cancer (NSCLC) and KRASG12C mutation (as determined by an FDA-approved test) who have received at least 1 systemic therapy. Adagrasib received breakthrough therapy and orphan drug designations for this indication.
At the same time, the FDA approved the QIAGEN therascreen KRAS RGQ PCR Kit (tissue) and the Agilent Resolution ctDx FIRST Assay (plasma) as companion diagnostics to adagrasib. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.
The approval of adagrasib was based on the results of KRYSTAL-1, a multicenter, single-arm, open-label clinical trial of patients with locally advanced or metastatic NSCLC and KRASG12C mutations. The efficacy was evaluated in 112 patients whose disease progressed during or after platinum-based chemotherapy and an immune checkpoint inhibitor, taken concurrently or sequentially. Patients received adagrasib 600 mg orally twice daily until disease progression or unacceptable adverse events.
The main efficacy measures were confirmed objective response rate (ORR) and duration of response (DOR). The ORR was 43% (95% confidence interval [CI], 34%-53%), and the median DOR was 8.5 months (95% CI, 6.2-13.8).
The most common (≥20%) adverse events were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and corrected QT interval prolongation. The most common (≥25%) laboratory abnormalities 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.