Introduction

Antineoplastic agent; irreversible and selective inhibitor of mutated KRAS p.G12C (KRAS G12C).

Uses for Sotorasib (Systemic)

Non-small Cell Lung Cancer

Treatment of locally advanced or metastatic KRAS G12C mutation-positive (as detected by an FDA-approved diagnostic test) non-small cell lung cancer (NSCLC) previously treated with ≥1 prior systemic therapy (designated an orphan drug by FDA for this use).

Accelerated approval based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit of sotorasib in confirmatory studies. In the principal efficacy study, objective response rate was 36% in patients with locally advanced or metastatic KRAS G12C mutated NSCLC previously treated with an anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibody, platinum-based combination chemotherapy, or both.

Sotorasib (Systemic) Dosage and Administration

General

Pretreatment Screening

• NSCLC: Confirmation of presence of KRAS G12C mutation (as determined by an FDA-approved test) in tumor or plasma specimens; if KRAS G12C mutation is not detected in a plasma specimen, retest with tumor tissue.

• Baseline liver function tests (i.e., ALT, AST, total bilirubin).

Patient Monitoring

• Monitor liver function tests (i.e., AST, ALT, total bilirubin) every 3 weeks for the first 3 months of therapy, then monthly or as clinically indicated; more frequent monitoring may be necessary in patients who develop hepatotoxicity.

• Monitor for new or worsening pulmonary symptoms (e.g., dyspnea, cough, fever) indicative of interstitial lung disease or pneumonitis.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), sotorasib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer orally at the same time each day without regard to food. Swallow tablets whole; do not crush, chew, or split.

Alternatively, for patients who are unable to swallow whole tablets, disperse tablets in 120 mL (4 ounces) of non-carbonated, room temperature water. Place total number of tablets for the dose (e.g., three 320 mg tablets or eight 120 mg tablets for total dose of 960 mg) into the water, without crushing, and stir or swirl for approximately 3 minutes to disperse the tablets into small pieces (complete dissolution will not occur). Resulting mixture may range in color from pale to bright yellow. Consume entire mixture immediately or within 2 hours of mixing without chewing residual tablet pieces. Rinse any residue remaining in the container with an additional 120 mL of water, stir or swirl again, and then consume immediately.

If a dose of sotorasib is missed by ≤6 hours, administer the prescribed dose as soon as it is remembered. If a dose is missed by >6 hours, administer the prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose.

If vomiting occurs after taking a dose, administer the next dose at the next scheduled time; do not administer an additional dose to replace the vomited dose.

Dosage

Adults

Non-small Cell Lung Cancer

Oral

960 mg once daily. Continue until disease progression or unacceptable toxicity occurs.

Dosage Modification

Dosing interruption and/or dosage reduction of sotorasib may be necessary based on individual safety and tolerability.

If dosage reduction from 960 mg once daily is necessary, reduce dosage to 480 mg once daily. If toxicity recurs on a dosage of 480 mg once daily, reduce dosage to 240 mg once daily. If toxicity recurs on a dosage of 240 mg once daily, discontinue drug.

Hepatotoxicity

If symptomatic grade 2 serum AST/ALT elevations occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

If grade 3 or 4 serum AST/ALT elevations occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

If serum AST or ALT concentrations >3 times the ULN and serum total bilirubin concentrations >2 times the ULN in the absence of other etiology, permanently discontinue sotorasib therapy.

Interstitial Lung Disease/Pneumonitis

If interstitial lung disease/pneumonitis of any grade is suspected, withhold sotorasib therapy. If interstitial lung disease/pneumonitis is confirmed, permanently discontinue sotorasib therapy.

GI Effects

If grade 3 or 4 nausea, vomiting, or diarrhea occurs despite appropriate supportive care, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

Other Toxicity

If other grade 3 or 4 toxicities occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

Special Populations

Hepatic Impairment

No dosage adjustment recommended in mild to moderate (Child Pugh class A or B) hepatic impairment. No specific dosage recommendations in severe (Child Pugh class C) hepatic impairment.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Contraindications

• None.

Warnings/Precautions

Hepatotoxicity

Hepatotoxicity, including drug-induced liver injury and hepatitis, reported. Median time to onset of serum ALT/AST elevations is 9 weeks.

Monitor liver function tests (i.e., serum ALT, AST, total bilirubin concentrations) prior to initiation of sotorasib, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated. More frequent monitoring may be necessary in patients who develop elevated aminotransferase and/or total bilirubin concentrations. If hepatotoxicity occurs, temporary interruption of sotorasib therapy, dosage reduction, or discontinuance of therapy may be necessary.

Interstitial Lung Disease/Pneumonitis

Interstitial lung disease/pneumonitis, sometimes fatal, reported. Median time to onset is 2 weeks.

Monitor patients for new or worsening pulmonary symptoms indicative of interstitial lung disease/pneumonitis (e.g., dyspnea, cough, fever). If interstitial lung disease/pneumonitis is suspected, promptly withhold sotorasib. Permanently discontinue drug if no other etiology is identified.

Specific Populations

Pregnancy

No available data in pregnant women.

No adverse developmental effects or embryo-lethality observed in animal studies.

Lactation

Not known whether sotorasib or its metabolites distribute into human milk or if the drug has any effect on milk production or the breast-fed infant. Because of the potential for adverse reactions to sotorasib in breast-fed infants, advise females not to breast-feed while receiving the drug and for 7 days after the drug is discontinued.

Pediatric Use

Safety and efficacy of sotorasib not established in pediatric patients.

Geriatric Use

Although data are limited, no clinically important differences in safety or efficacy observed between geriatric patients and younger adults.

Age (28–86 years) does not appear to have clinically important effects on pharmacokinetics of sotorasib.

Hepatic Impairment

Patients with hepatic impairment may experience more frequent adverse reactions.

Mild to moderate hepatic impairment (Child Pugh class A or B): dosage adjustments not necessary. Severe hepatic impairment (Child Pugh class C): safety of sotorasib unknown.

Renal Impairment

Mild to moderate renal impairment (estimated GFR ≥30 mL/minute per 1.73 m²): Pharmacokinetics not substantially altered; no dosage adjustment needed.

Severe renal impairment: Pharmacokinetics not studied.

Common Adverse Effects

Adverse effects (≥20%) include diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. Laboratory abnormalities (≥25%) include decreased lymphocytes, decreased hemoglobin, increased ALT and/or AST concentrations, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium concentrations.

General

Pretreatment Screening

• NSCLC: Confirmation of presence of KRAS G12C mutation (as determined by an FDA-approved test) in tumor or plasma specimens; if KRAS G12C mutation is not detected in a plasma specimen, retest with tumor tissue.

• Baseline liver function tests (i.e., ALT, AST, total bilirubin).

Patient Monitoring

• Monitor liver function tests (i.e., AST, ALT, total bilirubin) every 3 weeks for the first 3 months of therapy, then monthly or as clinically indicated; more frequent monitoring may be necessary in patients who develop hepatotoxicity.

• Monitor for new or worsening pulmonary symptoms (e.g., dyspnea, cough, fever) indicative of interstitial lung disease or pneumonitis.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), sotorasib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer orally at the same time each day without regard to food. Swallow tablets whole; do not crush, chew, or split.

Alternatively, for patients who are unable to swallow whole tablets, disperse tablets in 120 mL (4 ounces) of non-carbonated, room temperature water. Place total number of tablets for the dose (e.g., three 320 mg tablets or eight 120 mg tablets for total dose of 960 mg) into the water, without crushing, and stir or swirl for approximately 3 minutes to disperse the tablets into small pieces (complete dissolution will not occur). Resulting mixture may range in color from pale to bright yellow. Consume entire mixture immediately or within 2 hours of mixing without chewing residual tablet pieces. Rinse any residue remaining in the container with an additional 120 mL of water, stir or swirl again, and then consume immediately.

If a dose of sotorasib is missed by ≤6 hours, administer the prescribed dose as soon as it is remembered. If a dose is missed by >6 hours, administer the prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose.

If vomiting occurs after taking a dose, administer the next dose at the next scheduled time; do not administer an additional dose to replace the vomited dose.

Dosage

Adults

Non-small Cell Lung Cancer

Oral

960 mg once daily. Continue until disease progression or unacceptable toxicity occurs.

Dosage Modification

Dosing interruption and/or dosage reduction of sotorasib may be necessary based on individual safety and tolerability.

If dosage reduction from 960 mg once daily is necessary, reduce dosage to 480 mg once daily. If toxicity recurs on a dosage of 480 mg once daily, reduce dosage to 240 mg once daily. If toxicity recurs on a dosage of 240 mg once daily, discontinue drug.

Hepatotoxicity

If symptomatic grade 2 serum AST/ALT elevations occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

If grade 3 or 4 serum AST/ALT elevations occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

If serum AST or ALT concentrations >3 times the ULN and serum total bilirubin concentrations >2 times the ULN in the absence of other etiology, permanently discontinue sotorasib therapy.

Interstitial Lung Disease/Pneumonitis

If interstitial lung disease/pneumonitis of any grade is suspected, withhold sotorasib therapy. If interstitial lung disease/pneumonitis is confirmed, permanently discontinue sotorasib therapy.

GI Effects

If grade 3 or 4 nausea, vomiting, or diarrhea occurs despite appropriate supportive care, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

Other Toxicity

If other grade 3 or 4 toxicities occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

Special Populations

Hepatic Impairment

No dosage adjustment recommended in mild to moderate (Child Pugh class A or B) hepatic impairment. No specific dosage recommendations in severe (Child Pugh class C) hepatic impairment.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Metabolized principally by nonenzymatic conjugation and oxidative metabolism with CYP3A.

Sotorasib is a CYP3A4 substrate and inducer and a P-glycoprotein inhibitor. In vitro, may induce CYP2C8, CYP2C9, and CYP2B6. Inhibits breast cancer resistance protein (BCRP).

Does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Potent Inducers of CYP3A4: Possible decrease in systemic exposure to sotorasib and reduced sotorasib efficacy. Avoid concomitant use.

Substrates of CYP3A4: Possible decrease in plasma concentrations of CYP3A4 substrate drug and reduced efficacy of the CYP3A4 substrate. Avoid concomitant use with sensitive CYP3A4 substrates that have a narrow therapeutic index. If concomitant administration cannot be avoided, consult manufacturer's labeling of the sensitive CYP3A4 substrate drug for dosage adjustments of the CYP3A4 substrate.

Drugs Affecting or Affected by Transport Systems

Substrates of P-gp: Possible increase in plasma concentrations of the P-gp substrate drug and increased toxicity of the P-gp substrate. Avoid concomitant use with P-gp substrates where minimal concentration changes may lead to serious toxicities. If concomitant administration cannot be avoided, consult manufacturer's labeling of the P-gp substrate drug for dosage adjustments of the P-gp substrate.

Substrates of BCRP

Possible increase in plasma concentrations of the BCRP substrate drug and increased toxicity of the BCRP substrate. Monitor for adverse reactions of the BCRP substrate and potentially reduce the dosage if coadministered with sotorasib.

Drugs Affecting Gastric Acidity

Possible decrease in systemic exposure to sotorasib.

Avoid concomitant use with proton-pump inhibitors, H₂-receptor antagonists, and locally acting antacids. If concomitant use of a locally-acting antacid cannot be avoided, administer sotorasib 4 hours before or 10 hours after the locally-acting antacid.

Specific Drugs