On 12 December 2022, the US Food and Drug Administration (FDA) granted accelerated approval to adagrasib (Krazati, Mirati Therapeutics, Inc.), 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 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 tumour tissue should be tested.

Approval was based on KRYSTAL-1, a multicentre, single-arm, open-label clinical study (NCT03785249) which 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 v1.1, as evaluated by blinded independent central review, and duration of response (DoR). The ORR was 43% (95% confidence interval [CI] 34%, 53%) and median DoR was 8.5 months (95% CI 6.2, 13.8).

The most common adverse reactions (≥ 20%) were diarrhoea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnoea, oedema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased haemoglobin, 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.

This indication is approved under accelerated approval based on ORR and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted fast-track, breakthrough therapy, and orphan drug designation.

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.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA’s Oncology Center of Excellence Project Facilitate.