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Sotorasib

  • KRAS G12C inhibitorsKRAS G12C inhibitors
  • High alertAn error with this medicine can cause serious harm: double checks and protocols are used.

The first KRAS G12C inhibitor: it binds the mutant cysteine and locks KRAS «off»; for lung and colorectal cancers with this mutation.

Updated

Also called: AMG 510

Quick facts

Group
KRAS G12C inhibitors
Target
Mutant KRAS G12C (small GTPase)
Used for
Locally advanced · Metastatic colorectal cancer
Key effects
Diarrhoea · Fatigue · Musculoskeletal pain
Monitor
Test showing KRAS G12C before starting
ATC
L01XX73

No doses: the clinician sets them by the current guideline.

Mechanism of action

The crystal structure shows sotorasib covalently bound to cysteine 12 of human KRAS G12C in its GDP-bound (inactive) state.

Target in 3D: Mutant KRAS G12C (small GTPase). PDB structure 6OIM (RCSB PDB, public domain). View the structure at RCSB PDB

Sotorasib forms an irreversible covalent bond with the unique cysteine of KRAS G12C, locking the protein in its inactive GDP-bound state and preventing it from being reloaded with GTP. Downstream growth signalling stops. Normal KRAS, which lacks this cysteine, is spared, so off-target activity is minimal.

  1. G12C mutation leaves KRAS stuck «on» in the tumour
  2. Sotorasib bonds covalently to cysteine 12
  3. KRAS is locked in its inactive GDP state
  4. Growth signalling to the tumour stops

Indications

  • Locally advanced or metastatic non-small cell lung cancer with KRAS G12C after at least one systemic therapy. Lung cancer →
  • Metastatic colorectal cancer with KRAS G12C, with panitumumab, after fluoropyrimidine, oxaliplatin and irinotecan chemotherapy. Colorectal cancer →

Adverse effects

Common

  • Diarrhoea, nausea, vomiting
  • Fatigue
  • Musculoskeletal pain
  • Rash, dry skin
  • Cough, swelling of the limbs

Contraindications

  • No absolute contraindications in the label; used with caution in liver disease

Key interactions

Proton pump inhibitors and H2 blockers (e.g. omeprazole, famotidine)
Reduce absorption; combined use is avoided.
Antacids
Reduce absorption; doses are separated in time.
Strong CYP3A4 inducers (e.g. rifampicin)
Lower sotorasib levels.

What is monitored

  • Test showing KRAS G12C before starting
  • Liver tests regularly
  • New or worse cough, breathlessness or fever
  • Stool frequency and hydration

Administration and safety

  • Oral, once a day at about the same time; a dose vomited is not repeated that day.
  • The label describes a way to disperse the tablets in water for people who cannot swallow them.
  • Check the patient's acid-reducing medicines before starting.
  • Hazardous oral chemotherapy: handled with gloves and kept away from children; caregivers who are pregnant avoid handling it.

Pregnancy and breastfeeding

Pregnancy is discussed with the doctor and reported at once if it occurs; breastfeeding is avoided during treatment and for a short time after.

Nursing care

  • Review liver tests before refills and report jaundice, dark urine or right upper abdominal pain.
  • Ask about cough, breathlessness and fever.
  • Check for diarrhoea and dehydration.
  • Teaching: do not start antacids or heartburn medicines without asking; take it at the same time each day.

Pharmacokinetics

Absorption
Oral, with or without food; absorption falls with acid-reducing drugs.
Metabolism
Non-enzymatic conjugation and CYP3A.
Half-life
Short, about 5 hours.

Test yourself

Think of the answer, then tap the question to see it.

Which mutation must a tumour have to be treated with sotorasib?

KRAS G12C.

How does sotorasib bind its target?

Covalently and irreversibly to cysteine 12, locking KRAS in the inactive GDP-bound state.

Why are proton pump inhibitors avoided with sotorasib?

They reduce stomach acid and therefore sotorasib absorption.

Which antibody is combined with sotorasib in colorectal cancer?

Panitumumab, an anti-EGFR antibody.

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More Pharmacology questions →

Connections

← Back to the class: KRAS G12C inhibitors

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Sotorasib: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); Sotorasib - NCI (National Cancer Institute, 2026); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.