Sotorasib, an irreversible and selective inhibitor of mutated KRAS p.G12C ( KRAS G12C), is an antineoplastic agent.1, 2
Sotorasib is used as a single agent for the treatment of locally advanced or metastatic KRAS G12C mutation-positive non-small cell lung cancer (NSCLC) previously treated with at least one prior systemic therapy.1, 2, 6 An FDA-approved diagnostic test must be used for detection of KRAS G12C mutation.1, 3, 4 Sotorasib has been designated an orphan drug by FDA for the treatment of this cancer.9 The accelerated approval of sotorasib for this indication is based on overall response rate and duration of response.1 Continued approval for this indication may be contingent on verification and description of clinical benefit of sotorasib in confirmatory studies.1
The NSCLC indication for sotorasib is based principally on the results of a multicenter, noncomparative, open-label phase 1/2 study (CodeBreaK100) in 124 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.1, 6 In this study, patients received sotorasib 960 mg orally once daily until disease progression or unacceptable toxicity occurred.1, 6 The median age of patients was 64 years (range: 37-80 years), 50% were female, 82% of patients were White, 15% were Asian, 2% Black, 70% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1, 96% had stage 4 disease, 99% had nonsquamous histology, 81% were former smokers, 12% were current smokers, and 5% were never smokers.1, 6 Approximately one-half (43%) of patients had received one prior systemic therapy, 35% received 2 prior lines of therapy, and 22% received 3 prior lines of therapy.1, 6 The majority (81%) of patients received both platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 therapy.1, 6 Extra-thoracic sites of metastasis included bone (48%), brain (21%), and liver (21%).1 KRAS G12C mutations were identified in 70% of patients.1 The primary efficacy end point was objective response rate (as assessed by a blinded independent central review committee according to RECIST v1.1).1, 6 Secondary endpoints included duration of response, disease control, time to response, progression-free survival, and overall survival.6
At the time of analysis, the objective response rate was 36%; complete response was achieved in 2% of patients.1 The median time to response was 1.4 months (range: 1.2-10.1 months) and the median duration of response was 10 months.1, 6 Durable responses of 6 months or longer were reported in 58% of patients.1 At a median follow-up of 15.3 months, median progression-free survival and overall survival were 6.8 and 12.5 months, respectively.6
The efficacy of sotorasib versus docetaxel was evaluated in the open-label, randomized, multicenter, phase 3, CodeBreaK 200 trial.7 CodeBreaK 200 enrolled 345 adults with KRAS G12C-mutated advanced NSCLC, who had disease progression after prior therapy with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.7 Patients were randomly assigned to sotorasib 960 mg orally once daily or docetaxel 75 mg/m2 IV every 3 weeks.7 The primary study endpoint was progression-free survival as assessed by a blinded independent central review.7 Overall survival and overall response rate were among the key secondary endpoints.7
The mean age of patients was 64 years (range: 32-88 years) and the majority of patients in each group were male; approximately 83% of patients were White, 12% were Asian, and approximately 66% had an ECOG performance status of 1.7 Approximately 45% of patients in each group had received one prior systemic therapy, with the remaining patients administered ≥2 previous lines of therapy.7 Results revealed a significant improvement in progression-free survival with sotorasib as compared with docetaxel (5.6 versus 4.5 months) after a median follow-up of 17.7 months.7 Overall response rate was also significantly increased with sotorasib; however, overall survival was not different between the groups.7
KRAS is one of three isoforms of the RAS family of oncogenes and mutations in KRAS account for approximately 86% of RAS -mutant cancers.5 In patients with NSCLC adenocarcinoma, KRAS mutations are present in up to one-third of patients; however, the prevalence of KRAS mutations is lower in non-White populations.5 In patients with NSCLC, the most common KRAS mutation is a transversion of glycine and cysteine at codon 12 ( KRAS G12C) which results in enhanced proliferation and survival of tumor cells.2, 5 Patients harboring KRAS mutations generally have a poor prognosis compared to patients with epidermal growth factor receptor ( EGFR ) mutated NSCLC.10 Additionally, KRAS mutations are often associated with resistance to targeted therapies and poor outcomes in patients with cancer.2, 10
The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations, such as epidermal growth factor receptor ( EGFR ), b-Raf serine-threonine kinase ( BRAF ) V600E, and proto-oncogene receptor tyrosine kinase ( ROS1 ) mutations.12 The most recent update on advanced NSCLC with driver alterations states that clinicians may offer treatment with sotorasib or adagrasib to patients with advanced KRAS G12C NSCLC; however, the update notes that both agents are approved for patients who have received prior chemotherapy and/or anti-PD-(L)1.13 In the first-line setting, these patients should be administered standard therapy with an immune checkpoint inhibitor and/or chemotherapy following the nondriver alteration guidelines.13 Recommendations from a Canadian group are available specific to KRAS G12C-mutated advanced NSCLC, with first line treatment as immune checkpoint inhibitors with or without chemotherapy (i.e., platinum doublet).14 For patients progressing on first line therapy, platinum doublet (if not used as part of first line therapy) or sotorasib are preferred.14
Sotorasib is used, in combination with panitumumab, for the treatment of metastatic KRAS G12C mutation-positive colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.1 An FDA-approved diagnostic test must be used for detection of KRAS G12C mutation.1 Sotorasib has been designated an orphan drug by FDA for the treatment of this cancer.9
The colorectal cancer indication for sotorasib in combination with panitumumab is based principally on the results of a multicenter, open-label, randomized, active-controlled, phase 3 study (CodeBreak 300) in 160 adults with metastatic KRAS G12C mutated colorectal cancer previously treated with at least 1 prior line of chemotherapy.1, 15 In this study, patients were randomly assigned to either sotorasib 960 mg orally once daily and panitumumab 6 mg/kg IV every 2 weeks, sotorasib 240 mg orally once daily and panitumumab 6 mg/kg IV every 2 weeks, or investigator's choice of standard of care trifluridine/tipiracil or regorafenib.1, 6 Each treatment cycle was 28 days; treatment was continued until disease progression, lack of clinical benefit, or treatment intolerance.1, 15 The primary end point was progression-free survival, which was defined as time from randomization to disease progression or death from any cause, whichever occurred first.1, 15 Secondary end points included overall survival, objective response rate, and duration of response.1, 15
The median age of patients was 62 years (range: 34-82 years), 50% were female, 74% of patients were White, 17% were Asian, and 97% had an ECOG performance status of 1.1, 15 The median number of prior lines of therapy was 2.1 Patients administered sotorasib in combination with panitumumab experienced an improvement in median progression-free survival as compared to standard of care (5.6 months in the sotorasib 960 mg group and 3.9 months in the sotorasib 240 mg group versus 2.0 months in the standard of care group).15 The objective response rate was 26.4% in the 960 mg group, 5.7% in the 240 mg group, and 0% in the standard of care group.15 The median duration of response was 4.4 months.1, 15 At the time of data cutoff, overall survival data were not mature; 55 patients had died.15
Sotorasib is administered orally once daily at the same time each day without regard to food.1 The tablets should be swallowed whole and should not be chewed, crushed, or split.1
Alternatively, for patients who are unable to swallow whole tablets, sotorasib tablets may be dispersed in 120 mL (4 ounces) of non-carbonated, room temperature water.1 The total number of tablets for the dose should be placed into the water, without crushing, and stirred or swirled for approximately 3 minutes to disperse the tablets into small pieces (the tablets will not completely dissolve).1 The resulting mixture may range in color from pale to bright yellow.1 The entire mixture should be consumed immediately or within 2 hours of mixing without chewing residual tablet pieces.1 Any residue remaining in the container should be rinsed with an additional 120 mL of water, stirred or swirled again, and then consumed immediately.1
If a dose of sotorasib is missed by 6 hours or less, the prescribed dose should be taken as soon as it is remembered.1 If a dose is missed by more than 6 hours, the prescribed dose should be taken at the next scheduled time; an additional dose should not be administered to replace the missed dose.1
If vomiting occurs after taking a dose, the next dose should be taken at the next scheduled time; an additional dose should not be administered to replace the vomited dose.1
Store sotorasib tablets at 20-25ºC (excursions permitted between 15-30ºC).1
For the treatment of KRAS G12C-mutated, locally advanced or metastatic NCSLC in adults who have received at least one prior systemic therapy, the recommended adult dosage of sotorasib is 960 mg once daily (three 320 mg tablets, four 240 mg tablets, or eight 120 mg tablets).1 Therapy should be continued until either disease progression or unacceptable toxicity occurs.1
For the treatment of KRAS G12C-mutated, metastatic colorectal cancer in adults previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, the recommended adult dosage of sotorasib is 960 mg once daily (three 320 mg tablets, four 240 mg tablets, or eight 120 mg tablets) in combination with panitumumab.1 The first dose of sotorasib should be administered prior to the initial panitumumab infusion.1 Therapy should be continued until either disease progression or unacceptable toxicity occurs.1 Clinicians should refer to the panitumumab prescribing information for the recommended panitumumab dosage regimen.1
Dosing interruption and/or dosage reduction of sotorasib may be necessary based on individual safety and tolerability.1
In the principal efficacy study, interruption of therapy or dosage reduction because of adverse reactions was necessary in approximately 34 or 5%, respectively, of patients receiving sotorasib at the recommended dosage, most commonly for hepatotoxicity, diarrhea, musculoskeletal pain, nausea, or pneumonia.1 Permanent discontinuation of sotorasib was necessary in approximately 9% of patients, most commonly due to hepatotoxicity.1
If dosage reduction from 960 mg once daily is necessary, the dosage should be reduced to 480 mg once daily (two 240 mg or four 120 mg tablets).1 If the toxicity recurs on a dosage of 480 mg once daily, the dosage should be reduced to 240 mg once daily (one 240 mg or two 120 mg tablets).1 If the toxicity recurs on a dosage of 240 mg once daily, the drug should be discontinued.1
If sotorasib is administered with panitumumab, and sotorasib is temporarily withheld or permanently discontinued, panitumumab should also be temporarily withheld or permanently discontinued.1 Clinicians should refer to the panitumumab prescribing information for dosage modifications related to panitumumab adverse reactions.1 If panitumumab is permanently discontinued, sotorasib monotherapy may be continued.1 Below are dose modification guidelines related to adverse reactions associated with the use of sotorasib as a single agent.1
If serum AST or ALT concentrations are >3 times and up to 5 times the upper limit of normal (ULN) (or >3 times and up to 5 times baseline if baseline is abnormal) with symptoms OR serum AST or ALT concentrations are >5 times ULN (or >5 times baseline if baseline is abnormal), sotorasib therapy should be withheld until recovery to ≤3 times ULN or to ≤3 times baseline if baseline is abnormal.1 Once this occurs, sotorasib may be resumed at the next lower dose level.1
If serum AST or ALT concentrations exceed 3 times the ULN and serum total bilirubin concentrations exceed 2 times the ULN in the absence of other etiology, permanently discontinue sotorasib therapy.1 If an alternate etiology is identified, sotorasib therapy should not be resumed until AST/ALT and bilirubin levels have returned to baseline.1
Interstitial Lung Disease/Pneumonitis
If interstitial lung disease/pneumonitis of any grade is suspected, withhold sotorasib therapy.1 If interstitial lung disease/pneumonitis is confirmed, permanently discontinue sotorasib therapy.1
If grade 3 or 4 nausea, vomiting, or diarrhea occurs despite appropriate supportive care, withhold sotorasib therapy.1 When the toxicity resolves or improves to grade 1 or less or baseline, resume therapy at the next lower dosage.1
If other grade 3 or 4 toxicities occur, withhold sotorasib therapy.1 When the toxicity resolves or improves to grade 1 or less or baseline, resume therapy at the next lower dosage.1
No dosage adjustment is recommended in patients with mild to moderate (Child Pugh class A or B) hepatic impairment.1, 1 The manufacturer makes no specific dosage recommendations for patients with severe (Child Pugh class C) hepatic impairment.
The manufacturer makes no specific dosage recommendations.1
The manufacturer makes no specific dosage recommendations.1
Increased AST or ALT and hepatotoxicity, including drug-induced liver injury and hepatitis, have been reported in patients receiving sotorasib.1 In a pooled safety population of patients with NSCLC who received sotorasib 960 mg monotherapy, hepatotoxicity of any grade occurred in 27% of patients and was ≥grade 3 in 16% of patients.1 Among those with hepatotoxicity requiring dosage modifications, 64% required treatment with corticosteroids.1
In the pooled safety population of patients with NSCLC, increases in ALT and AST of any grade were reported in 17% of patients; grade 3 or 4 elevations were observed in 9% of patients, respectively.1 The median time to onset of serum ALT/AST elevations was 6.3 weeks (range: 0.4 to 42 weeks).1 Dosage modification (i.e., interruption of therapy, dosage reduction) or discontinuance of therapy was necessary in 9 or 2.7%, respectively, of patients receiving sotorasib because of elevations in serum aminotransferase concentrations.1 Drug-induced liver injury was reported in 1.6% of patients, with 1.3% experiencing ≥grade 3 injury.1
Results from the pooled safety population of patients with NSCLC also revealed that 40% of patients who received immunotherapy ≤3 months prior to sotorasib initiation experienced a hepatotoxicity event.1 This compared to 18% of patients who initiated sotorasib >3 months after the last dose of immunotherapy and 17% of patients who were never administered immunotherapy.1 Regardless of time from prior immunotherapy, the majority (94%) of hepatotoxicity events improved or resolved with sotorasib dosage modification, with or without corticosteroid treatment.1
In the pooled safety population of patients with colorectal cancer, increases in ALT and AST were reported in 7% of patients; grade 3 elevations were observed in 0.8% of patients.1 The median time to onset of serum ALT/AST elevations was 10 weeks (range: 2 to 22 weeks).1 Dosage interruption due to increased ALT or AST occurred in 2.4% of patients.1 Drug-induced liver injury was reported in 1.6% of patients, with 1.3% experiencing ≥grade 3 injury.1 Hepatotoxicity was reported in 15% of patients, of which 4.8% were grade 3.1 Hyperbilirubinemia was observed in 3.2% of patients, of which 2.4% were grade 3.1 The median time to onset of hyperbilirubinemia was 12 weeks (range: 0 to 29 weeks).1 Hyperbilirubinemia led to dose interruption in 1.6% of patients.1 Corticosteroids were administered to 21% of patients with hepatotoxicity.1
Monitor liver function tests (i.e., serum ALT, AST, alkaline phosphatase, 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.1 More frequent monitoring may be necessary in patients who develop elevated aminotransferase and/or total bilirubin concentrations.1 If hepatotoxicity occurs, temporary interruption of sotorasib therapy, dosage reduction, or discontinuance of therapy may be necessary.1 Clinicians should consider corticosteroid administration for hepatotoxicity management.1
Interstitial Lung Disease/Pneumonitis
Interstitial lung disease/pneumonitis, sometimes fatal, has been reported in patients receiving sotorasib.1 In a pooled safety population of patients with NSCLC, interstitial lung disease/pneumonitis occurred in 2.2% of patients; 1.1% of these cases were grade 3 or 4 in severity and one case resulted in death.1 The median time to onset was 8.6 weeks (range: 2.1 to 36.7 weeks).1 Discontinuance of sotorasib therapy was necessary in 1.3% of patients because of interstitial lung disease/pneumonitis.1
In a pooled safety population of patients with colorectal cancer, a single patient developed grade 1 interstitial lung disease/pneumonitis.1
Monitor patients for new or worsening pulmonary symptoms indicative of interstitial lung disease/pneumonitis (e.g., dyspnea, cough, fever).1 If interstitial lung disease/pneumonitis is suspected, promptly withhold sotorasib.1 Sotorasib therapy should be permanently discontinued if no other etiology is identified.1
There are no available data in pregnant women.1 Clinicians should refer to the panitumumab prescribing information for pregnancy risk and contraceptive information when sotorasib is administered with panitumumab.1
In animal development studies, adverse developmental effects or embryo-lethality were not observed in rats and rabbits at exposure levels up to 4.6 times the human exposure at the recommended dosage.1
It is not known whether sotorasib or its metabolites are distributed into human milk or if the drug has any effect on milk production or the breast-fed infant.1 Because of the potential for adverse reactions to sotorasib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 7 days after the last dose.1 Clinicians should refer to the panitumumab prescribing information for lactation information when sotorasib is administered with panitumumab.1
Safety and efficacy of sotorasib have not been established in pediatric patients.1
In the principal efficacy study evaluating sotorasib in patients with various tumor types, approximately 46% of patients receiving sotorasib were 65 years of age or older, and 10% were 75 years of age or older.1 Although data are limited, no clinically important differences in safety or efficacy were observed between geriatric patients and younger adults treated with sotorasib as a single agent in this study.1
In a pooled analysis of data from patients administered sotorasib in combination with panitumumab for metastatic colorectal cancer, 30% of patients were 65 years of age or older, and 9% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric patients and younger patients treated with sotorasib in combination with panitumumab.1
Age (28-86 years) does not appear to have clinically important effects on the pharmacokinetics of sotorasib.1
Patients with hepatic impairment may experience adverse reactions more frequently.1 Dosage adjustments in patients with mild or moderate hepatic impairment (Child Pugh class A or B) are not necessary.1
The effect of severe hepatic impairment (Child-Pugh class C) on the safety of sotorasib is unknown.1
Mild to moderate renal impairment (estimated glomerular filtration rate of 30 mL/minute per 1.73 m2 or higher) did not have clinically important effects on the pharmacokinetics of sotorasib; dosage adjustment in patients with mild or moderate renal impairment is not necessary.1
The pharmacokinetics of sotorasib have not been studied in patients with severe renal impairment.1
The most common adverse effects (≥20%) of single agent sotorasib in NSCLC include diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough.1 The most common 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.1
The most common adverse effects (≥20%) of combination therapy with sotorasib and panitumumab in colorectal cancer include rash, dry skin, diarrhea, stomatitis, fatigue, and musculoskeletal pain.1 The most common grade 3 or 4 laboratory abnormalities in ≥2 patients include decreased magnesium, potassium, and corrected calcium and increased potassium.1
Sotorasib is a cytochrome P-450 (CYP) 3A4 substrate and also induces CYP3A4.1
In vitro studies indicate that sotorasib may induce CYP2C8, CYP2C9, and CYP2B6.1 Sotorasib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.1
Sotorasib inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
Concomitant use of sotorasib with potent inducers of CYP3A4 may result in decreased systemic exposure to sotorasib and reduced sotorasib efficacy.1
When the potent CYP3A4 inducer rifampin (600 mg daily for 16 days) was administered concomitantly with sotorasib (960 mg orally for 3 days), peak plasma concentrations and AUC of sotorasib decreased by 35 and 51%, respectively.1, 10
Avoid concomitant use of sotorasib with potent inducers of CYP3A4.1
Concomitant use of sotorasib with drugs that are sensitive substrates of CYP3A4 may result in decreased plasma concentrations of the CYP3A4 substrate drug and reduced efficacy of the CYP3A4 substrate.1
When sotorasib was coadministered with the sensitive CYP3A4 substrate midazolam, peak plasma concentrations and AUC of midazolam decreased by 48 and 53%, respectively.1
Avoid concomitant use of sotorasib with sensitive CYP3A4 substrates that have a narrow therapeutic index.1 If concomitant administration cannot be avoided, clinicians should refer to the manufacturer's labeling of the sensitive CYP3A4 substrate drug for dosage adjustments of the CYP3A4 substrate.1
Drugs Affecting or Affected by Transport Systems
Concomitant use of sotorasib with drugs that are substrates of P-glycoprotein (P-gp) may result in increased plasma concentrations of the P-gp substrate drug and increased toxicity of the P-gp substrate.1
When sotorasib was coadministered with the P-gp substrate digoxin, peak plasma concentrations and AUC of digoxin increased by 91 and 21%, respectively.1
Avoid concomitant use with P-gp substrates where minimal concentrations changes may lead to serious toxicities.1 If concomitant administration cannot be avoided, clinicians should refer to the manufacturer's labeling of the P-gp substrate drug.1
Concomitant use of sotorasib with drugs that are substrates of BCRP may result in increased plasma concentrations of the BCRP substrate drug and an increased risk of adverse reactions.1
When sotorasib was coadministered with the BCRP substrate rosuvastatin, peak plasma concentrations and AUC of rosuvastatin increased by 70% and 34%, respectively.1
Monitor for adverse reactions of the BCRP substrate and potentially reduce the dosage if coadministered with sotorasib.1
Drugs Affecting Gastric Acidity
Concomitant use of sotorasib with drugs that affect gastric acidity may result in decreased systemic exposure to sotorasib.1
When a single dose of sotorasib was coadministered with repeat doses of the proton-pump inhibitor omeprazole (40 mg once daily for 6 days), peak plasma concentrations or AUC of sotorasib decreased by 65 or 57%, respectively, under fed conditions, and by 57 or 42%, respectively, under fasted conditions.1, 10 When the H2-receptor antagonist famotidine was administered 10 hours before and 2 hours after a single dose of sotorasib under fed conditions, peak plasma concentrations or AUC of sotorasib decreased by 35 or 38%, respectively.1
Avoid concomitant use with proton-pump inhibitors, H2-receptor antagonists, and locally-acting antacids.1 If concomitant use of a locally-acting antacid cannot be avoided, administer sotorasib 4 hours before or 10 hours after the locally-acting antacid.1
Sotorasib did not meaningfully alter the exposure of metformin (multidrug and toxin extrusion [MATE] transporter 1 and MATE2-K substrate) following coadministration.1
Sotorasib, an irreversible and selective inhibitor of mutated KRAS p.G12C ( KRAS G12C), is an antineoplastic agent.1, 2 Oncogenic mutations such as transversion of glycine and cysteine at codon 12 ( KRAS G12C) results in enhanced proliferation and survival of tumor cells.2, 5 Sotorasib forms an irreversible covalent bond with cysteine in the G12C transversion, which locks the mutant protein in an inactive form without affecting wild-type KRAS .1, 5
In vitro, sotorasib inhibits KRAS signaling and cell growth, and promotes apoptosis selectively in KRAS G12C-positive cell lines.1 Preclinical tumor models demonstrate that sotorasib rapidly binds to KRAS G12C and the irreversible covalent bond provides durable suppression of the mitogen-activated protein kinase (MAPK) signaling pathway.3 Sotorasib has demonstrated tumor regression, prolonged survival, and anti-tumor immunity in mouse tumor xenograft KRAS G12C models.1 In vitro and in vivo, the drug has also demonstrated inhibition of KRAS G12C with minimal detectable off-target activity.1
The recommended dosage of sotorasib produces nearly complete inhibition of KRAS G12C during therapy.5 The exposure-response relationship and time course of the pharmacodynamic response of sotorasib are unknown.1
The pharmacokinetics of sotorasib are non-linear and time-dependent over the dosage range of 180-960 mg once daily.1 Following oral administration, peak plasma concentrations of sotorasib are achieved in a median of 1 hour.1 Systemic exposure is comparable between film-coated tablets and film-coated tablets dispersed in water when administered under fasted conditions.1 Administration of sotorasib with a high-fat, high-calorie meal has no clinically important effect on the pharmacokinetics of sotorasib.1, 10 Sotorasib is 89% bound to plasma proteins in vitro.1 Sotorasib is metabolized principally by nonenzymatic conjugation and oxidative metabolism with CYP3A.1 Following oral administration of a single dose of radiolabeled sotorasib, 74% of the dose is eliminated in feces (53% as unchanged drug) and 6% is eliminated in urine (1% unchanged).1 The mean terminal elimination half-life of sotorasib is 5 hours.1 The mean AUC of a single 960 mg dose of sotorasib decreased by 25% in patients with moderate hepatic impairment (Child-Pugh class B) and increased by 4% in patients with severe hepatic impairment (Child-Pugh class C) compared to those with normal hepatic function.1 Age (28-86 years), sex, race/ethnicity, and body weight (36.8-157.9 kg) do not have clinically important effects on the pharmacokinetics of sotorasib.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Sotorasib can only be obtained through designated specialty pharmacies and distributors.8 Contact manufacturer for additional information.8
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 120 mg | Lumakras® | Amgen |
240 mg | Lumakras® | |||
320 mg | Lumakras® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Amgen. Lumakras® (sotorasib) film-coated tablets prescribing information. Thousand Oaks, CA; 2025 Jan.
2. Hong DS, Fakih MG, Strickler JH et al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med . 2020; 383:1207-1217. [PubMed 32955176]
3. Blair HA. Sotorasib: First Approval. Drugs . 2021; 81:1573-1579. [PubMed 34357500]
4. Food and Drug Administration. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). 2021 Sept 1. From FDA website. Accessed 2025 Feb 6. [Web]
5. Lindsay CR, Garassino MC, Nadal E et al. On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma. Lung Cancer . 2021; 160:152-165. [PubMed 34417059]
6. Skoulidis F, Li BT, Dy GK et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med . 2021; 384:2371-2381. [PubMed 34096690]
7. de Langen AJ, Johnson ML, Mazieres J, et al for the CodeBreak 200 investigators. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomized, open-label, phase 3 trial. Lancet . 2023;401:733-46.
8. Amgen Inc. Lumakras® (sotorasib) specialty pharmacy and distributors list. From the Lumakras® website. [Web]
9. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2025 Feb 6. [Web]
10. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 214665Orig1s000: Multi-discipline review. 2020 Jan. From FDA website. Accessed 2025 Feb 6. [Web]
12. Hanna N, Robinson A, Temin S, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) Joint Guideline update. J Clin Oncol . 2021;39:1040-1091. [PubMed 33591844]
13. Bazhenova L, Ismaila N, Rous FA, et al. Therapy for stage IV non-small-cell lung cancer wth driver alterations: ASCO living guideline. Version 2024.2. J Clin Oncol . 2024;42:e72-e86.
14. Cheema P, Banerji S, Blais N, et al. Canadian consensus recommendations on the management of KRAS G12C-mutated NSCLC. Curr Oncol . 2023;30:6473-6496. [PubMed 37504336]
15. Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med . 2023;389:2125-39.