Adagrasib Gains FDA Accelerated Approval for NSCLC with KRAS G12C Mutation

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KRAS is the most frequently mutated oncogene in cancer, and it is found in up to 25% of patients with non–small-cell lung cancer (NSCLC), with approximately 11% to 16% of tumors harboring the KRAS G12C mutation.1,2 This cancer subtype has been associated with poor prognosis and has long been considered untargetable.2 When properly functioning, the KRAS protein switches between an inactive form, GDP-RAS, and an active form, GTP-RAS.2 When it is in the GTP-RAS form, cell proliferation is reduced.2 Mutations block the reversible nature of the KRAS protein, resulting in uncontrolled cell growth.2

Adagrasib is a small-molecule inhibitor of KRAS G12C that selectively and irreversibly binds KRAS G12C in an inactive state.1 Studies on the KRAS G12C oncogene suggest that it may require a prolonged inhibition period due to its half-life of 24 hours.1 Adagrasib has a 23-hour half-life, favorable pharmacokinetic properties, and is able to penetrate the central nervous system; thus, it has piqued the interest of researchers in KRAS G12C–mutated NSCLC.1

The KRYSTAL-1 clinical trial investigated the efficacy of adagrasib in patients with NSCLC. This multicenter, open-label study enrolled 112 patients with locally advanced or metastatic NSCLC harboring KRAS G12C mutations. Eligible participants had disease progression on or after platinum-based chemotherapy plus an immune checkpoint inhibitor and received 600 mg of adagrasib orally twice a day until disease progression or toxicity became intolerable.

The main efficacy outcome was objective response rate, which was 43%. The median duration of response was 8.5 months. Diarrhea, nausea, decreased appetite, dyspnea, edema, vomiting, fatigue, musculoskeletal pain, cough, pneumonia, dizziness, constipation, abdominal pain, renal impairment, hepatotoxicity, and QTc interval prolongation were the most common adverse effects experienced by patients. Common laboratory abnormalities included increased aspartate aminotransferase, creatinine, alanine aminotransferase, and lipase and decreased lymphocytes, sodium, hemoglobin, albumin, platelets, magnesium, and potassium.

Based on these results, on December 12, 2022, the US Food and Drug Administration (FDA) granted accelerated approval for adagrasib at 600 mg orally twice a day until disease progression or unacceptable toxicity. In addition, the FDA approved the QIAGEN therascreen KRAS RGQ PCR kit and the Agilent Resolution ctDx FIRST Assay as companion diagnostic tests for adagrasib.


  1. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;387(2):120-131.
  2. Palma G, Khurshid F, Lu K, Woodward B, Husain H. Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes. NPJ Precis Oncol. 2021;5(1):98.

Source: FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. Published online December 12, 2022. Accessed January 31, 2023.

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