Adagrasib — Drug Monograph

Brand names: Krazati

Drug class: Other

Mechanism of Action

Covalent KRAS G12C inhibitor that irreversibly binds the switch-II pocket of KRAS in its GDP-bound (inactive) state, locking it in the off conformation and preventing downstream RAS/MAPK/PI3K signaling. CNS-penetrant with demonstrated intracranial activity.

FDA Indications

• KRAS G12C-mutated locally advanced or metastatic NSCLC after at least one prior systemic therapy (approved December 2022; KRYSTAL-1: 42.9% ORR)
• KRAS G12C-mutated metastatic colorectal cancer in combination with cetuximab after prior chemotherapy (approved 2024; KRYSTAL-10: 34% ORR vs chemotherapy)

Common Side Effects

• Nausea (58%)
• Diarrhea (51%)
• Vomiting (35%)
• Fatigue (32%)
• Musculoskeletal pain
• Hepatotoxicity (transaminase elevations)
• Peripheral edema
• Decreased appetite
• Constipation
• QTc prolongation

Clinical Pearl

Adagrasib demonstrates CNS penetration with documented intracranial activity, making it a preferred option for KRAS G12C NSCLC patients with brain metastases. It is active against a broader range of secondary mutations compared with sotorasib, though head-to-head data from CodeBreaK 300 showed sotorasib was not directly compared to adagrasib in a randomized trial.

Related Therapies & Mechanisms

• Sotorasib (Lumakras) — Other · NSCLC
• Bevacizumab (Avastin) — CRC
• Nivolumab (Opdivo) — NSCLC
• Pembrolizumab (Keytruda) — NSCLC