Detailed instructions for Sotorasib: indications, usage and dosage, side effects, precautions

Sotorasib, a specific inhibitor of oral KRAS G12C launched by Amgen in the United States, was approved for marketing for the first time under the accelerated channel of the US FDA on May 28, 2021. It was first used to treat patients with KRAS Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with G12C mutations mark the advent of oral targeted therapy for KRAS-mutated lung cancer. ‌

1. Sotorasib indications

‌1.1KRASG12C mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)‌

is indicated as a single agent for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) confirmed to have a KRASG12C mutation by an FDA-approved test and who have received at least one prior systemic therapy.

This indication was ultimately approved under accelerated approval by driving superior metrics of overall response rate (ORR) and duration of response (DOR) through an expedited approval process. However, approval of its continued clinical use will also depend on the results of further confirmatory trials that provide a more in-depth verification of its clinical use and a more accurate description of its clinical use.

‌1.2KRASG12C mutated metastatic colorectal cancer (mCRC)‌

Sotorasib combined with panitumumab The drug is suitable for the treatment of adult patients with metastatic colorectal cancer (mCRC) with KRASG12C mutations confirmed by FDA-approved testing, and the patients must have previously received fluorouracil, oxaliplatin and irinotecan-based chemotherapy.

The pictures are from public channels (such as the official website of the FDA, the official website of the original drug manufacturer, etc.) and are for reference only.

‌2. Sotorasib usage and dosage

‌2.1 Patient selection‌

1.‌KRASG12C mutated locally advanced or metastatic NSCLC‌

Patients are selected based on the presence of KRASG12C mutations in tumor or plasma samples.

If no mutation is detected in the plasma sample, tumor tissue needs to be tested.

2.‌KRASG12C mutated mCRC‌

Patients were selected based on the presence of KRASG12C mutations in tumor samples.

‌2.2 Recommended dosage and administration‌

(1)‌Monotherapy for KRASG12C mutated locally advanced or metastatic NSCLC‌

Sotorasiib ( The recommended dose of sotorasib is 960 mg (three 320 mg tablets or four 240 mg tablets or eight 120 mg tablets) administered orally once daily until disease progression or unacceptable toxicity.

(2)‌KRASG12C mutated mCRC combined with panitumumab treatment‌

The recommended dose of Sotorasib is 960 mg (three 320 mg tablets or four 240 mg tablets or eight 120 mg tablets), administered orally once daily in combination with panitumumab until disease progression or intolerable toxicity occurs.

The first dose of sotorasib should be completed before the first infusion of panitumumab.

(3)‌Precautions for administration‌

Take Sotorasib at a fixed time every day, with or without food.

Please swallow the tablet whole. Do not chew, crush or break it into pieces.

If you miss a dose for more than 6 hours, take the next dose the next day as originally planned. Do not take a double dose at the same time.

If vomiting occurs after taking the medicine, there is no need to take another dose. Take the next dose as planned the next day.

(4)‌Dosing Method for Patients with Dysphagia‌

Disperse Sotorasib tablets in 120 mL (4 ounces) of room temperature non-carbonated water (do not crush the tablets), stir or shake for about 3 minutes until the tablets are dispersed into small pieces (the tablets will not completely dissolve), and take immediately or within 2 hours.

The appearance of Sotorasib mixture can range from light yellow to bright yellow. After swallowing the solution, rinse the container with an additional 120 mL of water and drink.

But please stir it evenly before taking it immediately. You can also mix it thoroughly with an appropriate amount of water or other food within 10-15 minutes before taking it.

2.3 Dose adjustment of adverse reactions‌

Based on its unique dual effects on SAR, up to two dose reductions are allowed in the event of adverse reactions with Sotorasib.

However, for those patients who cannot tolerate the minimum daily dosage of 240 mg, we will discontinue Sotorasib.

‌Combination Precautions‌

When Sotorasib is used in combination with Panitumumab, if Sotorasib needs to be temporarily suspended or permanently discontinued, Panitumumab should be suspended or discontinued accordingly.

If panitumumab is permanently discontinued, sotorasib monotherapy can be continued.

‌2.4 Combination of Sotorasib and Acid Suppressants‌

Avoid the combination of Sotorasib and proton pump inhibitors (PPI) or H2 receptor antagonists.

If antacids must be used, sotorasib should be taken 4 hours before or 10 hours after topical antacid administration.

2.5 missed doses

If the interval between taking Sotorasib exceeds 6 hours, please resume treatment as prescribed the next day.

2.6 Sotorasib in combination with panitumumab

Patients taking sotorasib and panitumumab concurrently:

Take the first dose of sotorasib before the first panitumumab infusion.

Panitumumab should be discontinued when sotorasib is stopped or discontinued. ‌

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‌3.‌Dosage form and specifications of Sotorasib‌

‌320mg tablet‌: beige oval film-coated tablet, engraved with AMG on one side and 320 on the other side.

‌240mg Tablets‌: Yellow oval film-coated tablets engraved with AMG on one side and 240 on the other side.

‌120 mg tablet‌: Yellow oblong film-coated tablet, engraved with AMG on one side and 120 on the other side.

‌4.‌The contraindications of Sotorasib‌

are not clear yet.

‌5.‌Precautions for Sotorasib‌

‌5.1 Hepatotoxicity‌

Sotorasib may cause hepatotoxicity, manifested by an increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST), which may lead to drug-induced liver injury or hepatitis.

In the safety summary population of NSCLC patients receiving sotorasib 960 mg monotherapy, 27% of patients experienced hepatotoxicity, of which 16% were grade 3 or greater.

Among the patients with hepatotoxicity who required dose adjustment, 64% required glucocorticoid therapy.

In the same population, 17% of patients had elevated ALT/AST, of which 9% were grade 3 or above. The median time to first elevation in ALT/AST was 6.3 weeks (range: 0.4 to 42 weeks). 9% of patients required treatment interruption or reduction due to elevated ALT/AST, and 2.7% of patients permanently discontinued sotorasib due to elevated ALT/AST. The incidence of drug-induced liver injury was 1.6% (all grades), of which 1.3% were grade 3 or above.

(1) In the safety summary population of NSCLC patients receiving Sotorasib 960mg monotherapy (‌Influence of immunotherapy history‌):

Among patients who have recently received immunotherapy (≤3 months), 40% experienced hepatotoxic events.

Among patients who started sotorasib >3 months after the last immunotherapy, 18% developed hepatotoxicity.

17% of patients who had not received immunotherapy developed liver toxicity.

Conclusion: Regardless of the immunotherapy interval, 94% of hepatotoxic events were improved or alleviated by adjusting the dose of Sotorasib (with or without glucocorticoids).

(2) When CRC patients were treated with Sotorasib combined with panitumumab:

15% developed hepatotoxicity (Grade 3 accounted for 4.8%).

ALT/AST elevation occurred in 7% of patients (Grade 3 accounted for 0.8%), and the median onset of effect was 10 weeks (range 2-22 weeks).

Hyperbilirubinemia occurred in 3.2% (Grade 3, 2.4%), and the median onset of effect was 12 weeks (range 0-29 weeks).

21% of patients with hepatotoxicity received glucocorticoid therapy.

‌Monitoring requirements‌:

Test liver function (ALT/AST, alkaline phosphatase, total bilirubin) before treatment and regularly during treatment.

Test every 3 weeks for the first 3 months, and then once a month or increase the frequency according to clinical needs.

‌5.2 Interstitial lung disease (ILD)/pneumonia‌

Sotorasib may cause fatal ILD/pneumonitis.

(1) When NSCLC patients were treated with monotherapy:

2.2% developed ILD/pneumonitis (1.1% grade 3 or above), including 1 fatal case.

The median onset of effect was 8.6 weeks (range 2.1-36.7 weeks), and 1.3% of patients permanently discontinued the drug due to ILD/pneumonitis.

(2) During combined treatment of CRC:

Only one case of grade 1 ILD/pneumonia event

‌Processing principles‌:

Stop treatment immediately and investigate other causes, and permanently discontinue treatment after diagnosis.

6. Side effects of Sotorasib

6.1 Serious side effects of Sotorasib

While taking Sotorasib, if any of the following symptoms occur: Consult your doctor immediately if you experience any of the following side effects:

Chest pain or tightness in the chest, cough, dark urine, fever or chills, light-colored stools, loss of appetite, nausea or vomiting, sneezing, sore throat, stomach pain, difficulty breathing, unusual tiredness or weakness, yellowing of the eyes or skin, etc.

6.2 Other side effects of Sotorasib

While taking Sotorasib, some side effects are mild and may disappear on their own during the treatment process.

(1) Common side effects

If any of the following side effects persist, please consult your doctor:

Blistering, scabbing, inflamed, itchy or red skin, constipation, chapped, dry, flaky skin, diarrhea, difficulty moving, joint or bone pain, fatigue or loss of energy, muscle aches, cramps, pain or stiffness, flat or small raised rash on the skin, swelling of hands, ankles, feet or calves, swollen testicles, etc.

6.3 Side effects for medical staff to refer to

(1) General adverse events

Common adverse reactions

Common adverse reactions of Sotorasib include diarrhea, musculoskeletal Pain, nausea, fatigue, hepatotoxicity, and cough; the most common laboratory abnormalities include lymphopenia, decreased hemoglobin, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium, increased alkaline phosphatase, increased urinary protein, and decreased sodium.

Serious adverse reactions

Serious adverse reactions of Sotorasib include pneumonia, hepatotoxicity and diarrhea; the most common severe (Grade 3 or higher) adverse reactions are increased ALT, increased AST and diarrhea. Fatal adverse reactions include respiratory failure, pneumonia, cardiac arrest, heart failure, gastric ulcer, and pneumonia.

(2) Blood system

Very common (10% and above): lymphopenia (up to 48%), decreased hemoglobin (up to 43%), prolonged activated partial thromboplastin time (up to 23%), and anemia.

(3) Gastrointestinal tract

Very common (10% and above): diarrhea (up to 42%), nausea (up to 26%), vomiting (up to 17%), constipation (up to 16%), abdominal pain (including abdominal pain, upper abdominal pain, lower abdominal pain; up to 15%).

Not reported frequency: gastric ulcer.

(4) Liver

Very common (10% and above): elevated AST (up to 39%), elevated ALT (up to 38%), liver toxicity (including elevated ALT, elevated AST, elevated blood bilirubin, drug-induced liver injury, hepatitis, hepatotoxicity, abnormal liver function tests, elevated transaminases; up to 25%).

(5) Others

Very common (10% and above): decreased calcium (up to 35%), increased alkaline phosphatase (up to 33%), decreased sodium (up to 28%), fatigue (including fatigue, asthenia; up to 26%), decreased albumin (up to 22%), edema (including generalized edema, localized edema, edema, peripheral edema, periorbital edema, testicular edema; up to 15%), fever.

Common (1% to 10%): peripheral edema.

(6) Musculoskeletal

Very common (10% and above): musculoskeletal pain (including back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, limb pain; up to 35%), joint pain (up to 12%).

(7) Genitourinary system

Very common (10% and above): elevated urinary protein (up to 29%).

Common (1% to 10%): Urinary tract infection.

(8) Respiratory system

Very common (10% and above): cough (including cough, sputum production, upper airway cough syndrome; up to 20%), dyspnea (including dyspnea, exertional dyspnea; up to 16%), pneumonia (including pneumonia, aspiration pneumonia, bacterial pneumonia, staphylococcal pneumonia; up to 12%).

Unreported frequency: respiratory failure, pneumonia, interstitial lung disease (ILD).

(9) Cardiovascular system

Common (1% to 10%): hypertension.

Unreported frequency: cardiac arrest, heart failure.

(10) Metabolism

Very common (10% and above): decreased appetite (up to 13%).

Common (1% to 10%): hypokalemia, hyponatremia, hypocalcemia.

(11) Skin

Very common (10% and above): rash (including dermatitis, acneiform dermatitis, rash, maculopapular rash, pustular rash; up to 12%).

(12) Nervous system

Very common (10% and above): Headache.

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‌6. Drug interactions of Sotorasib‌

‌6.1 Effects of other drugs on Sotorasib‌

(1)‌Acid Suppressants‌

With different pH, the solubility of Sotorasib will also change accordingly, showing obvious pH-dependent characteristics. Since the presence of certain acid suppressants will affect the gastrointestinal absorption mechanism, its relative blood concentration in the body will be reduced, which may weaken its therapeutic effect.

‌Avoid combined use‌: proton pump inhibitors (PPI), H2 receptor antagonists, topical antacids.

When it cannot be avoided: Topical antacids should be used 4 hours before or 10 hours after sotorasib administration.

(2)‌Powerful CYP3A4 inducer‌

Sotorasib is a CYP3A4 substrate. Concomitant use of strong inducers will reduce their concentration and may reduce efficacy.

‌Concomitant use is prohibited‌: strong CYP3A4 inducers (such as rifampicin, phenytoin).

‌6.2 Effect of Sotorasib on other drugs‌

(1)‌CYP3A4 substrate‌

Sotorasib induces CYP3A4, and combined use will reduce the concentration of substrate drugs, which may lead to treatment failure.

‌Avoid combination‌: Sensitive substrates (such as tacrolimus) where small changes in concentration can lead to treatment failure.

(2)‌P-glycoprotein (P-gp) substrate‌

Sotorasib inhibits P-gp, and combined use will increase the plasma concentration of the substrate and may aggravate toxicity.

‌Avoid combined use‌: Substrates (such as digoxin) where small changes in concentration can lead to severe toxicity.

When it cannot be avoided: Reduce the dose of P-gp substrate according to the instructions.

(3)‌Breast cancer resistance protein (BCRP) substrate‌

Sotorasib inhibits BCRP, and combined use will increase the substrate concentration and may increase the risk of adverse reactions.

‌Monitoring recommendations‌: Closely monitor BCRP substrate adverse reactions during combined use, and adjust the dosage according to the instructions.

‌6.3 Metabolic effects of Sotorasib and other drugs

(1)‌Acid suppressant‌:

‌Omeprazole (PPI)‌:

When combined with repeated administration of a single dose of Sotorasib:

In the fed state, the Cmax of Sotorasib decreased by 65% and the AUC decreased by 57%.

In the fasting state, Cmax decreased by 57% and AUC decreased by 42%.

‌Famotidine (H2 receptor antagonist)‌:

After single administration (10 hours before eating and 2 hours after taking the drug), Cmax decreased by 35% and AUC decreased by 38%.

(2) Strong CYP3A4 inducer:

Rifampin: Repeated dosing combined with a single dose of Sotorasib resulted in a 35% decrease in Cmax and a 51% decrease in AUC.

(3) ‌Other drugs‌:

‌Itraconazole (strong CYP3A4/P-gp inhibitor)‌, ‌rifampicin (OATP1B1/1B3 inhibitor)‌ or ‌metformin (MATE1/2-K substrate)‌: There is no clinically significant effect on sotorasib exposure after combined use.

CYP3A4 substrate (midazolam): Cmax decreased by 48% and AUC decreased by 53%.

‌P-gp substrate (digoxin)‌: Cmax increased by 91%, AUC increased by 21%.

‌MATE1/2-K substrate (metformin)‌: No significant change in exposure.

‌BCRP substrate (rosuvastatin)‌: Cmax increased by 70%, AUC increased by 34%.

(4)‌In vitro studies‌

‌CYP enzyme induction‌: May induce CYP2C8, 2C9, and 2B6, but does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6.

‌7. Sotorasib’s use in special populations‌

‌7.1 Medication during pregnancy‌

Clinical data on the use of Sotorasib in pregnant women are limited.

(1) Animal studies show that

No developmental toxicity or embryonic lethality was observed when rats and rabbits were given oral Sotorasib during the organogenesis period at doses up to 4.6 times the human clinical dose of 960 mg (calculated by AUC).

When using panitumumab in combination, please refer to the pregnancy risks and contraceptive recommendations in its package insert.

(2)‌Background risk in the U.S. population‌

In clinically confirmed pregnancies, the estimated risks of major birth defects and miscarriage are 2%-4% and 15%-20%, respectively.

(3)‌Rat embryo-fetal development test‌

Daily oral administration of Sotorasib during the organogenesis period at a dose of 540 mg/kg (approximately 4.6 times the human exposure at the clinical dose of 960 mg) resulted in maternal toxicity but did not affect embryonic development or survival.

‌(4) Rabbit embryo-fetal development test‌

Daily oral administration of 100 mg/kg (approximately 2.6 times the human exposure at the clinical dose of 960 mg) during the organogenesis period resulted in a decrease in fetal weight and metacarpal ossification number, which was related to the increase in maternal weight and decrease in food intake, but did not affect survival rate.

(5)AUC

The area under the blood drug concentration-time curve reflects drug exposure.

(6) Dose unit conversion

Animal dose and human equivalent dose are based on the AUC ratio.

‌7.2 Medication during lactation‌‌

There is no data on the distribution of Sotorasib or its metabolites in human milk, and there are no studies on the effects on lactating infants or milk secretion.

In view of the potential for serious adverse reactions in nursing infants, it is recommended that women stop breastfeeding during treatment with Sotorasib and within 1 week after the last dose.

When using panitumumab in combination, please refer to the lactation medication recommendations in its package insert.

‌7.3 Pediatric Drugs‌

Recent studies have a preliminary understanding of its safety and effectiveness in adult patients, but the safety and effectiveness of Sotorasib in pediatric patients still need to be further clarified and confirmed through more adequate clinical trials.

‌7.4 Medication for the Elderly‌

‌According to the research data of CodeBreaK100, 46% of the 357 patients who received 960 mg of Sotorasib were over 65 years old, and even 10% of the patients were over 75 years old. Elderly patients can be treated with this drug as a single drug. There were no overall differences in safety and effectiveness between older patients and younger patients.

According to the latest combination treatment data, among 132 patients with KRASG12C mutated pangastric cancer (mCRC) who received the combination treatment of Sotorasib and panitumumab, 30% of the patients were over 65 years old, reaching 9% of the elderly patients over 75 years old. There is no significant difference in safety and efficacy between elderly patients (≥65 years old) and young patients.

‌7.5 Hepatic Impairment‌

‌Mild to Moderate Impairment (Child-Pugh Class A/B)‌: No dosage adjustment is required.

‌Severe Injury (Child-Pugh Class C)‌: Safety data are unknown, and more frequent monitoring of adverse reactions (such as liver toxicity) is required. For dose adjustment details, please refer to the dose adjustment table in Dosage and Administration.

8. Sotorasib clinical pharmacology‌

‌8.1 Mechanism of action‌

(1) Targetability‌

Sotorasib is a specific inhibitor of the KRASG12C mutant, which is a tumor-limited oncogenic form.

(2)‌Covalent binding‌

Form an irreversible covalent bond with the unique cysteine ​​of KRASG12C, locking the protein in an inactive state, blocking downstream signaling without affecting wild-type KRAS.

(3)‌Anti-tumor effect‌

In in vitro/in vivo experiments, it only inhibits the KRASG12C tumor cell line and induces cell apoptosis.

With the help of studies on mouse transplanted tumor models, not only can the tumor regression and survival period be significantly prolonged, but the host's anti-tumor immunity can also be significantly activated.

(4)‌Potential of combination therapy‌

In KRASG12C mutant colorectal cancer (CRC), epidermal growth factor receptor (EGFR) activation is one of the resistance mechanisms.

In patient-derived CRC xenograft tumor models, combined use of the EGFR inhibitor panitumumab can enhance anti-tumor activity.

‌8.2 Pharmacodynamics‌

(1)‌Exposure-response relationship‌:

Currently unclear.

(2)‌Cardiac Electrophysiology‌:

However, at its recommended dosage, Sotorasib has no significant effect on the QT interval of the heart (both <20ms).

(3)‌Physical and chemical properties and preparations of drugs‌

‌PH-dependent solubility‌

‌pKa value‌: 8.06 (base), 4.56 (acidic group).

‌Solubility Change‌: Within the pH range of 1.2 to 6.8, the water solubility decreases from 1.3mg/mL to 0.03mg/mL.

‌Preparation composition‌

‌Specifications‌: 320mg, 240mg, 120mg film-coated tablets.

‌Excipients‌:

‌Tablet core‌: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate.

‌Coating‌: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc; 320mg tablets additionally contain iron oxide yellow/red.

8.3 Pharmacokinetics‌

(1)‌Absorption‌

‌Peak time‌: The median plasma peak concentration is 1 hour.

‌Food impact‌: High-fat and high-calorie meals (containing 800-1000 kcal, protein 150 kcal, carbohydrate 250 kcal, fat 500-600 kcal) can increase Sotolasibu AUC0-24h by 25%.

(2)‌Distribution‌

‌Apparent distribution volume‌: average 211L at steady state (coefficient of variation CV: 135%).

‌Plasma protein binding rate‌: In vitro experiments show that the binding rate of plasma proteins to itself reaches 89%.

(3)‌Elimination‌

‌Terminal half-life‌: average 5 hours (standard deviation SD: 2).

‌Steady-state clearance‌: When 960mg is administered once daily, the average is 26.2L/hr (CV: 76%).

(4)‌Metabolism and excretion‌

‌Metabolic pathways‌: The main metabolic pathways include non-enzymatic conjugated metabolism and oxidative metabolism through CYP3A.

‌Excretion ratio‌: After a single dose of radioactive label, 74% is excreted in the feces (53% of the original form) and 6% is excreted in the urine (1% of the original form). ‌

9. Sotorasib’s storage conditions‌

Temperature requirements: 20°C to 25°C (68°F to 77°F), short-term fluctuations allowed to 15°C-30°C (59°F-86°F)

10. Patient advisory information for Sotorasib

Recommend patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). ‌

‌Hepatotoxicity‌

Inform patients who experience symptoms of abnormal liver function (such as jaundice, nausea, etc.) to contact their medical provider immediately.

‌Interstitial Lung Disease (ILD)/Pneumonia‌

Inform patients that they need to report new or worsening respiratory symptoms (e.g., cough, difficulty breathing) to their healthcare provider immediately.

Breastfeeding

It is recommended that women not breastfeed while receiving sotorasib and for 1 week after the last dose. For information regarding breastfeeding when sotorasib is used with panitumumab, see full prescribing information for panitumumab.

Drug Interactions

Advise patients to inform their healthcare provider of all concomitant medications, including prescription drugs, over-the-counter drugs, vitamins, dietary supplements, and herbal products. Inform patients to avoid use of proton pump inhibitors and H2 receptor antagonists while taking sotorasib.

If coadministration with antacids cannot be avoided, inform patients to take sotorasib 4 hours before or 10 hours after taking a locally acting antacid.