Classification
- Targeted therapy / KRAS inhibitor
- First-in-class, small-molecule, irreversible inhibitor of KRAS G12C mutation.
Mechanism of Action
- KRAS normally cycles between inactive (GDP-bound) and active (GTP-bound) states.
- In KRAS G12C–mutated cancers, the protein is locked in an active oncogenic state, continuously signaling via the RAS–RAF–MEK–ERK pathway.
- Sotorasib binds irreversibly to the cysteine residue at position 12, trapping KRAS in its inactive GDP-bound form → inhibits downstream signaling and tumor growth.
Indications (FDA / Health Canada approved)
- NSCLC (Non–Small Cell Lung Cancer):
- For adults with KRAS G12C–mutated, locally advanced or metastatic NSCLC
- After at least one prior systemic therapy (chemotherapy or immunotherapy).
- Investigational/clinical trials: CRC, pancreatic, biliary tract, and other solid tumors with KRAS G12C mutation.
Dosing
- Standard adult dose:
- 960 mg orally once daily (8 × 120 mg tablets)
- Swallow whole, with or without food.
- Treatment duration: until disease progression or unacceptable toxicity.
Adverse Effects (Common)
- Gastrointestinal: diarrhea, nausea, vomiting, constipation
- Hepatic: increased ALT/AST, hepatotoxicity
- Constitutional: fatigue, decreased appetite
- Respiratory: cough, dyspnea
- Others: musculoskeletal pain
Serious adverse effects:
- Hepatotoxicity (monitor LFTs before and during therapy)
- Interstitial lung disease / pneumonitis (rare but potentially fatal)
Drug Interactions
- Metabolism: CYP3A4 substrate
- Avoid strong CYP3A4 inducers (e.g., rifampin, phenytoin, St. John’s Wort).
- Avoid acid-reducing agents (PPIs, H2 blockers) → reduced absorption.
- Potential for interaction with P-gp substrates.
Monitoring
- Baseline and regular LFTs (ALT, AST, bilirubin)
- Monitor for pulmonary symptoms (dyspnea, cough → ILD risk)
- Monitor for GI tolerance and nutritional status
- Response to treatment via imaging (RECIST criteria)
Pharmacist Clinical Pearls