FDA Grants Accelerated Approval to Adagrasib for KRAS G12C–Variant Non-Small Cell Lung Cancer
On December 12, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc) to adagrasib (Krazati®), a RAS GTPase family inhibitor, for adult patients with KRAS G12C–variant locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, and who have received at least one prior systemic therapy.
FDA also approved the QIAGEN therascreen KRAS RGQ PCR kit (tissue) and the Agilent Resolution ctDx FIRST Assay (plasma) as companion diagnostics for adagrasib. If the test does not detect a variant in a plasma specimen, test the tumor tissue.
Approval was based on KRYSTAL-1, a multicenter, single-arm, open-label clinical trial (NCT03785249) which included patients with locally advanced or metastatic NSCLC with KRAS G12C variants. Efficacy was evaluated in 112 patients whose disease had 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 they experienced 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 reported in at least 20% of patients treated with adagrasib were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and prolonged QTc interval. The most common laboratory abnormalities reported in at least 25% of patients treated with adagrasib were decreased lymphocytes, sodium, hemoglobin, albumin, platelets, magnesium, and potassium and increased aspartate aminotransferase, creatinine, alanine aminotransferase, and lipase.
The recommended adagrasib tablet dose is 600 mg orally twice daily until patients experience disease progression or unacceptable toxicity.
View the full prescribing information for adagrasib (https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216340s000lbl.pdf).
The indication was approved under accelerated approval based on overall response rate and DOR. Continued approval for the indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
The review used the Assessment Aid (https://www.fda.gov/about-fda/oncology-center-excellence/assessment-aid), a voluntary submission from the applicant to facilitate the FDA’s assessment.
The application was granted fast-track, breakthrough therapy, and orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics).
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System (https://www.accessdata.fda.gov/scripts/medwatch/index.cfm) or by calling 800-FDA-1088.
For assistance with single-patient investigational new drug applications, contact OCE’s Project Facilitate (https://www.fda.gov/about-fda/oncology-center-excellence/project-facilitate) at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov (mailto:OncProjectFacilitate@fda.hhs.gov).