Classification
- Targeted therapy / KRAS inhibitor
- Small-molecule, covalent inhibitor of KRAS G12C mutation.
- Structurally distinct from sotorasib, with a longer half-life and some CNS penetration (important in NSCLC with brain metastases).
Mechanism of Action
- Binds irreversibly to the cysteine residue at codon 12 in KRAS G12C.
- Locks KRAS in the inactive GDP-bound state, preventing downstream RAS–RAF–MEK–ERK signaling → reduces proliferation and survival of tumor cells.
Indications (FDA / Health Canada approval)
- NSCLC (Non–Small Cell Lung Cancer):
- For adults with KRAS G12C–mutated, locally advanced or metastatic NSCLC
- After at least one prior systemic therapy.
- Ongoing studies in colorectal cancer (CRC), pancreatic cancer, and other solid tumors with KRAS G12C mutation.
Dosing
- 600 mg orally twice daily (total daily dose = 1200 mg).
- Swallow whole, with or without food.
- Continue until disease progression or unacceptable toxicity.
Adverse Effects (Common)
- GI: diarrhea, nausea, vomiting, constipation, abdominal pain
- General: fatigue, decreased appetite, edema
- Respiratory: cough, dyspnea
- Liver: increased ALT/AST
- Other: QT prolongation (unique vs sotorasib)
Serious adverse effects:
- Hepatotoxicity → monitor LFTs
- Interstitial lung disease / pneumonitis (rare, but serious)
- QT prolongation and arrhythmias (ECG monitoring recommended in some patients)
Drug Interactions
- CYP3A4 substrate → avoid strong inducers/inhibitors
- P-gp substrate → caution with P-gp inhibitors
- QT-prolonging agents → use with caution
- Acid-reducing agents may impact absorption (consult labeling for timing guidance).
Monitoring
- Baseline and periodic LFTs (ALT, AST, bilirubin)
- ECG and electrolytes in patients at risk of QT prolongation
- Monitor for GI tolerance (diarrhea, nausea)
- Watch for pulmonary toxicity (dyspnea, cough, fever → ILD concern)
- Disease response via imaging
Pharmacist Clinical Pearls
- Half-life ~24 hours, allowing BID dosing and potentially more stable KRAS inhibition than sotorasib.
- Demonstrated CNS activity (important in NSCLC with brain metastases).
- Higher GI toxicity (especially nausea/diarrhea) vs sotorasib → antiemetic support may be needed.
- Alternative option if patients progress on or cannot tolerate sotorasib.