Sotorasib (Lumakras): A Comprehensive Guide to the First KRAS G12C-Targeted Inhibitor

　　1.Drug Overview

　　Sotorasib(brand name:Lumakras;development code:AMG-510)is an oral small-molecule targeted agent developed by Amgen.Classified as a RAS GTPase family inhibitor,it received accelerated approval from the U.S.Food and Drug Administration(FDA)on May 28,2021,becoming the first-ever targeted therapy directed against the KRAS G12C mutation—a breakthrough that ended more than four decades of KRAS being considered"undruggable."In January 2025,the FDA further approved sotorasib in combination with panitumumab for previously treated KRAS G12C-mutant metastatic colorectal cancer,broadening its clinical utility.

　　Sotorasib is supplied as oral tablets in strengths of 320 mg,240 mg,and 120 mg,taken once daily.Before initiating therapy,patients must undergo an approved genetic test to confirm the presence of a KRAS G12C mutation in their tumor.Safety and efficacy in pediatric patients have not been established.

　　2.Mechanism of Action

　　KRAS mutations are among the most prevalent oncogenic drivers in solid tumors,with the G12C subtype accounting for approximately 78%of RAS mutations in non-small cell lung cancer.This mutation locks the KRAS protein in a constitutively active state,perpetually transmitting proliferative signals through the RAF-MEK-ERK pathway.

　　Sotorasib forms an irreversible covalent bond with the cysteine residue of the KRAS G12C mutant protein,trapping it in the inactive GDP-bound conformation.This blocks downstream proliferative signaling,suppresses tumor cell growth,and induces apoptosis,while sparing wild-type KRAS in normal cells due to its high selectivity.

　　In colorectal cancer,combining sotorasib with the EGFR inhibitor panitumumab has demonstrated superior efficacy over monotherapy,overcoming feedback activation of the EGFR pathway that limits single-agent activity.

　　3.FDA-Approved Indications

　　Non-Small Cell Lung Cancer(NSCLC):Sotorasib as monotherapy is indicated for adult patients with locally advanced or metastatic NSCLC harboring a KRAS G12C mutation who have received at least one prior systemic therapy.This indication was granted under accelerated approval based on objective response rate and duration of response;continued approval is contingent upon confirmatory trials demonstrating sustained clinical benefit.

　　Metastatic Colorectal Cancer(mCRC):Sotorasib in combination with panitumumab is indicated for adult patients with KRAS G12C-mutant mCRC who have progressed following standard chemotherapy regimens containing fluoropyrimidines,oxaliplatin,and irinotecan.

　　4.Dosage and Administration

　　The recommended dose of sotorasib is 960 mg taken orally once daily at approximately the same time each day,with or without food.Tablets must be swallowed whole with water;they must not be chewed,crushed,or split.

　　When used with panitumumab for CRC:Sotorasib should be taken orally first,followed by panitumumab intravenous infusion.If sotorasib is withheld or discontinued,panitumumab should also be paused or stopped concurrently.

　　For patients unable to swallow tablets whole:Place the prescribed dose in approximately 120 mL of room-temperature,non-carbonated water.Do not crush the tablets.Gently swirl for about 3 minutes until the tablets disperse(they will not fully dissolve).The resulting liquid should appear pale to bright yellow.Consume within 2 hours without chewing any fragments.Then add another 120 mL of water to the same container,swirl,and drink to ensure the full dose is taken.

　　Interaction with acid-reducing agents:H₂-receptor antagonists or local antacids should be administered at least 4 hours before or 10 hours after sotorasib.Proton pump inhibitors should be avoided.

　　Vomiting:If vomiting occurs after a dose,do not retake the dose.Resume the regular schedule the following day.

　　Missed dose:If a dose is missed by fewer than 6 hours,take it as soon as remembered.If more than 6 hours have elapsed,skip the missed dose and take the next dose at the scheduled time.Never take a double dose to compensate.

　　Dose modifications:For intolerable adverse reactions,the physician may reduce the dose from 960 mg to 480 mg or 240 mg daily,or temporarily/permanently discontinue treatment.

　　5.Adverse Reactions

　　Common adverse reactions with sotorasib monotherapy in NSCLC:Diarrhea,musculoskeletal pain,nausea,fatigue,cough,and hematologic abnormalities(e.g.,decreased hemoglobin,lymphopenia).

　　Common adverse reactions with sotorasib plus panitumumab in mCRC:Rash,dry skin,diarrhea,stomatitis(oral ulcers),fatigue,musculoskeletal pain,and electrolyte/hematologic abnormalities(e.g.,hypokalemia,hypomagnesemia).

　　6.Serious Warnings and Precautions

　　Hepatotoxicity:Sotorasib can cause elevations in liver enzymes and bilirubin;severe drug-induced liver injury has been reported.Monitor liver function(ALT,AST,total bilirubin)every 3 weeks during the first 3 months of treatment,then monthly or as clinically indicated.Patients presenting with jaundice,dark urine,clay-colored stools,persistent nausea,right upper quadrant pain,marked appetite loss,or unusual bruising/bleeding should seek immediate medical attention.Depending on severity,the physician may withhold,reduce,or permanently discontinue sotorasib and consider systemic corticosteroids.

　　Interstitial Lung Disease(ILD)/Pneumonitis:Sotorasib may cause pulmonary inflammation that can be life-threatening.New or worsening dyspnea,cough,or fever during treatment warrants urgent evaluation.If ILD/pneumonitis is suspected or confirmed,sotorasib must be discontinued immediately and appropriate treatment initiated.

　　7.Pre-Treatment Considerations and Special Populations

　　Before starting therapy,inform your physician of any history of liver disease,pre-existing lung conditions(e.g.,interstitial lung disease,pulmonary fibrosis),and all concurrent medications.

　　Pregnancy and breastfeeding:Animal data suggest potential embryo-fetal toxicity.Adequate human data are lacking.Breastfeeding is not recommended during treatment and for at least one week after the last dose.Women of childbearing potential should use effective contraception during therapy and for one week after discontinuation.

　　Pediatric use:Safety and efficacy in patients under 18 years of age have not been established.

　　8.Storage

　　Store sotorasib tablets at room temperature between 20°C and 25°C(excursions permitted between 15°C and 30°C).The bottle is equipped with a child-resistant cap.Keep out of reach of children,and protect from moisture and direct sunlight.