Adagrasib Receives FDA Approval for KRAS G12C Mutation-Positive Lung Cancer

For adults whose tumours carry KRAS G12C, a specific genetic mutation, who have received at least one previous systemic treatment and have  non-small cell lung cancer (NSCLC), the targeted medicine adagrasib (Krazati, Mirati Therapeutics, Inc.) received accelerated FDA (US Food and Drug Administration) approval on 12 December 2022. For tumours with any KRAS mutation, which account for around 25% of mutations in non-small cell lung cancer, this is the second targeted therapy. KRAS G12C mutations represent approximately  13% of mutations in non-small cell lung cancer.

What Is KRAS?

KRAS is known as one of the most frequently mutated  oncogenes  in human cancer. KRAS mutations drive the growth and proliferation of multiple cancer types through the RAS/MAPK signalling cascade.

The most common KRAS G12 mutations are G12D (36%), G12C (14%) and G12V (23%).

KRAS mutations were once considered impossible to target or treat, but  Lumakras, containing sotorasib proved effective against KRAS G12C-mutated non-small cell lung cancer and received FDA (US Food and Drug Administration) approval. In May 2021, sotorasib became the first KRAS-targeted cancer treatment approved for use in the United States.

Below are the cancer types in which KRAS G12C mutations are most commonly seen: 

What Is Adagrasib?

Adagrasib is a RAS GTPase inhibitor that selectively and irreversibly inhibits KRAS G12C, locking cancer cells to guanosine diphosphate and preventing their growth and proliferation.

With a 24-hour half-life, broad tissue distribution and dose-dependent pharmacokinetics, oral adagrasib at 600 mg twice daily inhibits KRAS gene activity in cancer cells.

Alongside this approval, the FDA approved the QIAGEN therascreen KRAS RGQ PCR Kit for tissue and the Agilent Resolution ctDx FIRST Assay for blood as companion diagnostic tools for Krazati. If no mutation is detected in a blood-based liquid biopsy, tumour tissue should be tested.

FDA Approval Based on the KRYSTAL-1 Study

Approval was based on KRYSTAL-1, a multicentre, single-arm, open-label trial in locally advanced or metastatic NSCLC with KRAS G12C mutations. Efficacy was assessed in 112 patients whose disease progressed during or after platinum-based chemotherapy and an immune checkpoint inhibitor, given concurrently or sequentially. Patients received oral adagrasib 600 mg twice daily until progression or unacceptable adverse effects.

The main efficacy outcomes were confirmed objective response rate and duration of response, assessed by blinded independent central review.

• The objective response rate was 43% (95% CI: 34%, 53%), and
• Median response duration was 8.5 months (95% CI: 6.2, 13.8).

The most common adverse effects (≥ 20%) were diarrhoea, nausea, fatigue, vomiting, musculoskeletal pain, liver injury, renal failure, shortness of breath, oedema (swelling), reduced appetite, cough, pneumonia, dizziness, constipation, abdominal pain and QTc interval prolongation on ECG. The most common laboratory abnormalities (≥ 25%) were reduced lymphocytes, increased aspartate aminotransferase (AST), reduced sodium and haemoglobin, increased creatinine, reduced albumin, increased alanine aminotransferase (ALT) and lipase, and reduced platelets, magnesium and potassium.

The recommended adagrasib tablet dose is 600 mg twice daily until progression or unacceptable adverse effects.