Sotorasib — Drug Monograph

Brand names: Lumakras

Drug class: Other

Mechanism of Action

Covalent, irreversible small-molecule inhibitor of KRAS G12C (AMG 510) that selectively binds the mutant cysteine-12 residue in the switch-II pocket of KRAS GDP-bound state, locking KRAS in its inactive conformation and blocking downstream proliferative signaling. Specific to G12C; no activity against G12D or G13D mutations.

FDA Indications

• KRAS G12C-mutated locally advanced or metastatic NSCLC after at least one prior systemic therapy (first FDA-approved KRAS inhibitor, May 2021; CodeBreaK 100: 37.1% ORR; CodeBreaK 200 vs docetaxel: superior PFS)

Common Side Effects

• Diarrhea (34%)
• Musculoskeletal pain (28%)
• Nausea (27%)
• Fatigue (25%)
• Hepatotoxicity (ALT/AST elevation 20–30%)
• Cough
• Decreased appetite
• Constipation

Clinical Pearl

Sotorasib is KRAS G12C-specific with no cross-reactivity to G12D or G13D. Concomitant proton pump inhibitor use reduces bioavailability and should be avoided. Hepatotoxicity (grade 3+ in ~8%) requires close weekly LFT monitoring for the first 3 months.

Related Therapies & Mechanisms

• Adagrasib (Krazati) — Other · NSCLC
• Arsenic Trioxide (Trisenox) — Other
• Asparaginase (L-asparaginase, E. coli) (Elspar) — Other
• Avutometinib/Defactinib (Avmapki Fakzynja Co-Pack) — Other