What Is Adagrasib (Krazati)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA approved: Yes (first approval date: December 12, 2022)
• Brand name: Krazati 
• Active ingredient: Adagrasib
• Route of administration: Oral
• Class: Signal transduction inhibitor, KRAS G12C inhibitor
• Category: Targeted agent
• Manufacturer: : Mirati Therapeutics 
• Distribution in Turkey: None
• Cancers for which it is approved:
  • Non-Small Cell Lung Cancer
  • Metastatic Colorectal Cancer

What Is Adagrasib?

Containing adagrasib, Krazati is a selective, irreversible inhibitor targeting cancer cells with a KRAS G12C mutation. By preventing activation of the KRAS G12C protein, it blocks intracellular signaling and prevents tumor cell proliferation.

What Is KRAS?

KRAS is known to be one of the most frequently mutated  oncogenes  in human cancer. KRAS mutations drive the growth and proliferation of multiple cancers through the RAS/MAPK signaling cascade.

KRAS mutations were once considered untargetable and untreatable. However,  Lumakras, containing sotorasib , was shown to be effective against KRAS G12C-mutated NSCLC and received FDA approval in May 2021. Sotorasib thus became the first approved KRAS-targeted cancer treatment.

The most common KRAS G12 mutations are G12D (36%),  G12C (14%) , and G12V (23%). Among KRAS mutations, approved targeted treatment is currently available only for G12C.

How Does Krazati Work?

• Krazati is a selective, irreversible inhibitor targeting the KRAS G12C mutation.
• It covalently binds to the unique cysteine site of the KRAS G12C protein, locking it in an inactive GDP-bound state and thereby blocking downstream signaling.
• The KRAS G12C mutation occurs in 14% of non-small cell lung cancers (NSCLC), 3-4% of colorectal cancers (CRC), 2% of pancreatic cancers, and other solid tumors.
• The medicine supports antitumor immunity by creating a pro-inflammatory environment in the tumor microenvironment .

FDA Approval History:

• December 12, 2022: Krazati received accelerated FDA approval for advanced or metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation.
• June 21, 2024: Krazati received FDA approval with cetuximab for metastatic colorectal cancer (CRC) with a KRAS G12C mutation.

Licensing of Adagrasib in Turkey

Krazati, containing adagrasib, has not yet been licensed by Turkey's Ministry of Health.

Is Adagrasib Reimbursed?

It is not reimbursed by Turkey's Social Security Institution (SGK).

Mechanisms of Resistance

• Secondary KRAS Mutations: Additional mutations in the KRAS protein may alter the medicine's binding sites, reducing Krazati's effectiveness.
• High-Level Amplification of the KRAS G12C Allele: High-level amplification of the KRAS G12C allele may reactivate intracellular signaling pathways, weakening the medicine's effect.
• Polyclonal RAS-MAPK Reactivation: Reactivation of RAS-MAPK signaling through multiple routes may reduce Krazati's effectiveness.
• MET Mutations and Amplification: Mutations and excessive amplification of the MET gene may contribute to resistance to Krazati.
• Oncogenic Fusions: Oncogenic fusions within the cell may reduce Krazati's effect and lead to resistance.

Absorption

After oral administration, plasma levels peak in approximately 6 hours. Food does not affect absorption.

Distribution

Krazati is 98% bound to plasma proteins. With regular use, blood levels stabilize in approximately 8 days.

Metabolism

Krazati is metabolized in the liver by CYP3A4 enzymes. Elimination occurs mainly through feces (75%). Renal elimination accounts for only 5% of the administered dose. The half-life is approximately 23 hours.

Dose Range

The recommended dose is 600 mg orally twice daily, with or without food.

Drug Interactions

• CYP3A4 Inhibitors: Medicines such as ketoconazole, itraconazole, and erythromycin may slow Krazati metabolism, increasing blood levels and the risk of toxicity.
• CYP3A4 Inducers: Medicines such as phenytoin, carbamazepine, and rifampin may accelerate Krazati metabolism, reducing its effectiveness.
• P-Glycoprotein (P-gp) Substrates: Medicines such as digoxin, verapamil, and diltiazem may affect Krazati's plasma levels and increase the risk of adverse effects.
• Medicines That Prolong the QTc Interval: Medicines such as amiodarone and sotalol may prolong the QTc interval, increasing the risk of serious heart rhythm disturbances.
• CYP2C9 and CYP2D6 Substrates: Using Krazati with medicines such as warfarin and metoprolol may alter their effects.

Conditions Requiring Caution

1. Hepatic Impairment: No dose adjustment is required in patients with mild or moderate hepatic impairment. However, liver function should be monitored regularly during the first 3 months of treatment.
2. Renal Impairment: No dose adjustment is required in patients with mild or moderate renal impairment.
3. Liver Function Tests: Liver function tests should be monitored during treatment, particularly monthly for the first 3 months.
4. Gastrointestinal Symptoms: Patients should be monitored closely for gastrointestinal adverse effects such as diarrhea, nausea, and vomiting.
5. ECG and Electrolyte Monitoring: ECGs should be performed regularly, and electrolyte levels checked during treatment.
6. Pulmonary Symptoms: Patients should be monitored closely for pulmonary symptoms such as cough and shortness of breath, and treatment reassessed if severe symptoms occur.
7. Pregnancy and Breastfeeding: There are insufficient data on Krazati use during pregnancy. Breastfeeding should therefore be avoided during and after treatment.

Adverse Effects

From most common to least common, adverse effects include:

• Gastrointestinal adverse effects (diarrhea, nausea/vomiting)
• Pulmonary toxicity (increased cough, shortness of breath, pulmonary infiltrates, interstitial lung disease, pneumonia)
• Hepatotoxicity (increased ALT/AST and serum bilirubin)
• Fatigue and loss of appetite
• QTc prolongation and associated serious heart rhythm disturbances
• Arthralgia and musculoskeletal pain
• Abnormalities such as decreased lymphocyte counts, decreased hemoglobin, increased ALT and AST enzymes, hypokalemia, and hyponatremia.