Sotorasib is the first approved KRASG12C targeted inhibitor for the treatment of non-small cell lung cancer (NSCLC) carrying this mutation. The clinical application guidelines are described in detail from the aspects of mechanism of action, indications, medication regimen, and monitoring points.

1. Mechanism of action and target characteristics

(1) Targeted inhibition: By covalently binding to the switch II pocket of KRASG12C mutant protein, its inactive GDP binding conformation is locked, blocking downstream signal transduction.

(2) Selectivity: It only acts on KRASG12C mutant tumor cells and has minimal effect on wild-type KRAS, significantly reducing off target toxicity.

2 Indications and patient screening

(1) Applicable population: Patients with locally advanced or metastatic NSCLC confirmed to have KRASG12C mutation through testing, and who have received at least one systemic treatment.

(2) Testing requirements: FDA approved companion diagnostic testing (such as QIAGENtharscreenKRASRGQPCRKit) must be used to confirm the mutation status.

3 Standard Medication Plans

(1) Dosage: Take 960mg orally once a day, whole tablet, at a fixed time to improve compliance.

(2) Course of treatment: Continue medication until disease progression or intolerable toxicity occurs, with a median progression free survival of approximately 6.8 months.

(3) Adjustment: If grade 3-4 toxicity occurs, the administration should be suspended. After recovery, the dosage should be reduced in steps from 480mg to 240mg.

4 Key Adverse Reaction Management

(1) Hepatotoxicity: The incidence rate is about 25%, and liver function needs to be monitored monthly. AST/ALT>3 × ULN with elevated bilirubin requires permanent discontinuation of medication.

(2) Interstitial lung disease: incidence rate is about 0.8%, and new respiratory symptoms require immediate suspension of medication and evaluation.

(3) Gastrointestinal reactions: 3-4 grade diarrhea/vomiting require temporary suspension of medication, symptomatic treatment should be given, and dosage should be reduced before restarting.

5 Precautions for Special Groups

(1) Liver injury: Child Pugh grade C should be avoided, grade B should be used with caution and strengthened monitoring.

(2) Pregnancy period: It has embryonic toxicity. Before taking medication, it is necessary to confirm the pregnancy status and take contraceptive measures.

(3) Elderly individuals aged 65 and above do not need to adjust their dosage, but attention should be paid to drug interactions with comorbidities.