Sotorasib

Sotorasib
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]

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Overview

Sotorasib is an inhibitor of the RAS GTPase that is FDA approved for the treatment of *adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy.

• LUMAKRAS, in combination with panitumumab, is indicated for the treatment of adult patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC), as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.. Common adverse reactions include ==Single agent in NSCLC:==
• The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

• In combination with panitumumab in CRC: The most common adverse reactions (≥ 20%) in clinical trials of LUMAKRAS in combination with panitumumab are rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities in ≥ 2 patients (4.3%) were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

KRAS G12C-mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

• As a single agent, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy.
  • This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

KRAS G12C-mutated Metastatic Colorectal Cancer (mCRC)

• In combination with panitumumab, for the treatment of adult patients with KRAS G12C-mutated mCRC as determined by an FDA approved-test, who have received prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy.

Recommended dosage as a single agent for NSCLC and in combination with panitumumab for mCRC:

• 960 mg orally once daily.
• Swallow tablets whole with or without food.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sotorasib in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sotorasib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Sotorasib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sotorasib in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sotorasib in pediatric patients.

Contraindications

None.

Warnings

Hepatotoxicity

• LUMAKRAS can cause hepatotoxicity and increased alanine aminotransferase (ALT) or increased aspartate aminotransferase (AST) which may lead to drug-induced liver injury and hepatitis.

• In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg ,hepatotoxicity occurred in 27% of patients, of which 16% were Grade ≥ 3. Among patients with hepatotoxicity who required dosage modifications, 64% required treatment with corticosteroids.

• In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, 17% of patients who received LUMAKRAS had increased ALT/increased AST; of which 9% were Grade ≥ 3. The median time to first onset of increased ALT/AST was 6.3 weeks (range: 0.4 to 42). Increased ALT/AST leading to dose interruption or reduction occurred in 9% of patients treated with LUMAKRAS. LUMAKRAS was permanently discontinued due to increased ALT/AST in 2.7% of patients. Drug-induced liver injury occurred in 1.6% (all grades) including 1.3% (Grade ≥ 3).

In this pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg, a total of 40% patients with recent (≤ 3 months) immunotherapy prior to starting LUMAKRAS had an event of hepatotoxicity. An event of hepatotoxicity was observed in 18% of patients who started LUMAKRAS more than 3 months after last dose of immunotherapy and in 17% of those who never received immunotherapy. Regardless of time from prior immunotherapy, 94% of hepatotoxicity events improved or resolved with dosage modification of LUMAKRAS, with or without corticosteroid treatment.

• In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab ,hepatotoxicity occurred in 15% of patients, of which 4.8% were Grade 3. A total of 7% of patients who received LUMAKRAS had increased ALT or increased AST, of which 0.8% were Grade 3. The median time to first onset of increased ALT or increased AST was 10 weeks (range: 2 to 22). Increased ALT or increased AST leading to dose interruption occurred in 2.4% of patients. A total of 3.2% of patients who received LUMAKRAS had hyperbilirubinemia, of which 2.4% were Grade 3. The median time to first onset of hyperbilirubinemia was 12 weeks (range: 0, 29). Hyperbilirubinemia leading to dose interruption occurred in 1.6% of patients. Among patients with hepatotoxicity, 21% received corticosteroids.

• Monitor liver function tests (ALT, AST, alkaline phosphatase and total bilirubin) prior to the start of LUMAKRAS, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop transaminase and/or bilirubin elevations. Withhold, reduce the dose or permanently discontinue LUMAKRAS based on severity of the adverse reaction. Consider administering systemic corticosteroids for the management of hepatotoxicity.

Interstitial Lung Disease (ILD)/Pneumonitis

• LUMAKRAS can cause ILD/pneumonitis that can be fatal.

• In the pooled safety population of patients with NSCLC who received single agent LUMAKRAS 960 mg.ILD/pneumonitis occurred in 2.2% of patients, of which 1.1% were Grade ≥ 3, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 8.6 weeks (range: 2.1 to 36.7 weeks). LUMAKRAS was permanently discontinued due to ILD/pneumonitis in 1.3% of LUMAKRAS-treated patients. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LUMAKRAS in patients with suspected ILD/pneumonitis and permanently discontinue LUMAKRAS if no other potential causes of ILD/pneumonitis are identified.

• In the pooled safety population of patients with CRC who received LUMAKRAS 960 mg in combination with panitumumab, 1 patient experienced a Grade 1 event of ILD/pneumonitis.

Adverse Reactions

Clinical Trials Experience

• Hepatotoxicity.
• Interstitial Lung Disease (ILD)/Pneumonitis.

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LUMAKRAS as a single agent at 960 mg orally once daily until disease progression or unacceptable toxicity in 549 patients with NSCLC with KRAS G12C mutation in the following trials: CodeBreaK 200 (NCT04303780), CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883) and CodeBreaK 105 (NCT04380753). Among these 549 patients who received LUMAKRAS, 44% were exposed for 6 months or longer and 21% were exposed for greater than one year.
• The pooled safety population described in WARNINGS AND PRECAUTIONS also reflects exposure to LUMAKRAS 960 mg once daily in combination with panitumumab in 126 patients who received LUMAKRAS in combination with panitumumab for mCRC in CodeBreaK 300 (NCT05198934) and CodeBreaK 101 (NCT04185883). Among the 126 patients who received LUMAKRAS 960 mg in combination with panitumumab, 40% were exposed for 6 months or longer and 10% were exposed for greater than one year.

Metastatic Non-Small Cell Lung Cancer

• The safety of LUMAKRAS was evaluated in a subset of patients with KRAS G12C-mutated locally advanced or metastatic NSCLC in CodeBreaK 100 . Patients received LUMAKRAS 960 mg orally once daily until disease progression or unacceptable toxicity (n = 204). Among patients who received LUMAKRAS, 39% were exposed for 6 months or longer and 3% were exposed for greater than one year.
• The median age of patients who received LUMAKRAS was 66 years (range: 37 to 86); 55% female; 80% White, 15% Asian, and 3% Black.
• Serious adverse reactions occurred in 50% of patients treated with LUMAKRAS. Serious adverse reactions in ≥ 2% of patients were pneumonia (8%), hepatotoxicity (3.4%), and diarrhea (2%). Fatal adverse reactions occurred in 3.4% of patients who received LUMAKRAS due to respiratory failure (0.8%), pneumonitis (0.4%), cardiac arrest (0.4%), cardiac failure (0.4%), gastric ulcer (0.4%), and pneumonia (0.4%).
• Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 9% of patients. Adverse reactions resulting in permanent discontinuation of LUMAKRAS in ≥ 2% of patients included hepatotoxicity (4.9%).
• Dosage interruptions of LUMAKRAS due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients were hepatotoxicity (11%), diarrhea (8%), musculoskeletal pain (3.9%), nausea (2.9%), and pneumonia (2.5%).
• Dose reductions of LUMAKRAS due to an adverse reaction occurred in 5% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included increased ALT (2.9%) and increased AST (2.5%).
• The most common adverse reactions (≥ 20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

Adverse Reactions (≥ 10%) of Patients with KRAS G12C-Mutated NSCLC who Received LUMAKRAS in CodeBreaK 100*

Adverse Reactions (≥ 10%) of Patients with KRAS G12C-Mutated NSCLC who Received LUMAKRAS in CodeBreaK 100

Table 4 summarizes the selected laboratory adverse reactions observed in CodeBreaK 100.

Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with KRAS G12C-Mutated NSCLC who Received LUMAKRAS in CodeBreaK 100

Metastatic Colorectal Cancer

• The safety of LUMAKRAS in combination with panitumumab was evaluated in the CodeBreaK 300 study.Patients with KRAS G12C-mutated mCRC received LUMAKRAS 960 mg orally once daily in combination with panitumumab 6 mg/kg intravenously (IV) once every 2 weeks (N = 47), *LUMAKRAS 240 mg orally once daily in combination with panitumumab 6 mg/kg IV once every 2 weeks (N = 50), or the investigator's choice of standard of care (SOC) trifluridine/ tipiracil or regorafenib (N = 50). Among patients who received LUMAKRAS 960 mg orally once daily in combination with panitumumab, 36% were exposed to LUMAKRAS for greater than 6 months and 6% were exposed for greater than 12 months.
• The median age of patients who received LUMAKRAS 960 mg in combination with panitumumab arm was 63 years (range: 37-79 years); 38% were age 65 years or older; 49% were female; 79% were White and 13% were Asian.
• Serious adverse reactions occurred in 26% of patients receiving LUMAKRAS 960 mg in combination with panitumumab. Serious adverse reactions in ≥ 2 patients receiving LUMAKRAS 960 mg in combination with panitumumab were sepsis (6%) and intestinal obstruction (4.3%). Fatal adverse reactions occurred in 2 patients (4.3%) receiving LUMAKRAS 960 mg in combination with panitumumab, consisting of cardiac arrest and sepsis (1 patient each).
• Permanent discontinuation of LUMAKRAS due to an adverse reaction occurred in 1 patient for decreased corrected calcium.
• Dosage interruptions of LUMAKRAS due to an adverse reaction occurred in 26% of patients. Adverse reactions which required dosage interruption in ≥ 2 patients were rash, hepatotoxicity and intestinal obstruction.
• A dose reduction of LUMAKRAS due to an adverse reaction occurred in 1 patient for nausea.
• The most common adverse reactions (≥ 20%) in patients receiving LUMAKRAS 960 mg in combination with panitumumab were rash, dry skin, diarrhea, stomatitis, fatigue and musculoskeletal pain.
• The most common Grade 3-4 laboratory abnormalities in ≥ 2 patients (4.3%) were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium.

Table 5 and Table 6 summarize the adverse reactions and laboratory abnormalities, respectively, identified in CodeBreaK 300.

Adverse Reactions (≥ 10%) in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in Combination with Panitumumab in CodeBreaK 300

Adverse Reactions (≥ 10%) in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in Combination with Panitumumab in CodeBreaK 300

Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with KRAS G12C-Mutated mCRC who Received LUMAKRAS 960 mg in combination with panitumumab in CodeBreaK 300

Postmarketing Experience

There is limited information regarding Sotorasib Postmarketing Experience in the drug label.

Drug Interactions

Effects of Other Drugs on LUMAKRAS

Acid-Reducing Agents

• The solubility of sotorasib is pH-dependent. Coadministration of LUMAKRAS with gastric acid-reducing agents decreased sotorasib concentrations, which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with proton pump inhibitors (PPIs), H2 receptor antagonists, and locally acting antacids. If coadministration with an acid-reducing agent cannot be avoided, administer LUMAKRAS 4 hours before or 10 hours after administration of a locally acting antacid.

Strong CYP3A4 Inducers

• Sotorasib is a CYP3A4 substrate. Coadministration of LUMAKRAS with a strong CYP3A4 inducer decreased sotorasib concentrations.which may reduce the efficacy of sotorasib. Avoid coadministration of LUMAKRAS with strong CYP3A4 inducers.

Effects of LUMAKRAS on Other Drugs

CYP3A4 Substrates

• Sotorasib is a CYP3A4 inducer. Coadministration of LUMAKRAS with a CYP3A4 substrate decreased its plasma concentrations ,which may reduce the efficacy of the substrate. Avoid coadministration of LUMAKRAS with CYP3A4 sensitive substrates, for which minimal concentration changes may lead to therapeutic failures of the substrate. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information.

P-glycoprotein (P-gp) Substrates

• Sotorasib is a P-gp inhibitor. Coadministration of LUMAKRAS with a P-gp substrate increased its plasma concentrations ,which may increase the adverse reactions of the substrate. Avoid coadministration of LUMAKRAS with P-gp substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the P-gp substrate dosage in accordance with its Prescribing Information.

Breast Cancer Resistance Protein (BCRP) Substrates

• Sotorasib is a BCRP-inhibitor. Coadministration of LUMAKRAS with a BCRP substrate increased its plasma concentrations ,which may increase the risk of adverse reactions of the substrate. When coadministered with LUMAKRAS, monitor for adverse reactions of the BCRP substrate and decrease the BCRP substrate dosage in accordance with its Prescribing Information.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

• There are no available data on LUMAKRAS use in pregnant women. In rat and rabbit embryo-fetal development studies, oral sotorasib did not cause adverse developmental effects or embryo-lethality at exposures up to 4.6 times the human exposure at the 960 mg clinical dose.

• Refer to the Full Prescribing Information of panitumumab for pregnancy risk information and contraception recommendations when LUMAKRAS is administered in combination with panitumumab.

• In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

• In a rat embryo-fetal development study, once daily oral administration of sotorasib to pregnant rats during the period of organogenesis resulted in maternal toxicity at the 540 mg/kg dose level (approximately 4.6 times the human exposure based on area under the curve (AUC) at the clinical dose of 960 mg). Sotorasib did not cause adverse developmental effects and did not affect embryo-fetal survival at doses up to 540 mg/kg.

• In a rabbit embryo-fetal development study, once daily oral administration of sotorasib during the period of organogenesis resulted in lower fetal body weights and a reduction in the number of ossified metacarpals in fetuses at the 100 mg/kg dose level (approximately 2.6 times the human exposure based on AUC at the clinical dose of 960 mg), which was associated with maternal toxicity including decreased body weight gain and food consumption during the dosing phase. Sotorasib did not cause adverse developmental effects and did not affect embryo-fetal survival at doses up to 100 mg/kg.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sotorasib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Sotorasib during labor and delivery.

Nursing Mothers

Risk Summary

• There are no data on the presence of sotorasib or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LUMAKRAS and for 1 week after the last dose.

• Refer to the Full Prescribing Information of panitumumab for lactation recommendations when LUMAKRAS is administered in combination with panitumumab.

Pediatric Use

• The safety and effectiveness of LUMAKRAS have not been established in pediatric patients.

Geriatic Use

• Of the 357 patients with any tumor type who received LUMAKRAS 960 mg orally once daily in CodeBreaK 100, 46% were 65 and over, and 10% were 75 and over. No overall differences in safety or effectiveness were observed between older patients and younger patients treated with LUMAKRAS as a single agent.

• In a pooled analysis of 132 patients who received LUMAKRAS 960 mg in combination with panitumumab for KRAS G12C-mutated mCRC, 30% were 65 and over while 9% were 75 and over. No overall differences in safety or efficacy were observed between older patients (≥ 65 years of age) compared to younger patients, treated with LUMAKRAS 960 mg in combination with panitumumab.

Gender

There is no FDA guidance on the use of Sotorasib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Sotorasib with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Sotorasib in patients with renal impairment.

Hepatic Impairment

• No dosage modification is recommended in patients with mild to moderate hepatic impairment (Child-Pugh A or B).

• The effect of severe hepatic impairment (Child-Pugh C) on the safety of LUMAKRAS is unknown. Monitor for sotorasib adverse reactions in patients with hepatic impairment more frequently since these patients may be at increased risk for adverse reactions including hepatotoxicity.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Sotorasib in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Sotorasib in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Sotorasib Administration in the drug label.

Monitoring

There is limited information regarding Sotorasib Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Sotorasib and IV administrations.

Overdosage

There is limited information regarding Sotorasib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Sotorasib Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Sotorasib Mechanism of Action in the drug label.

Structure

There is limited information regarding Sotorasib Structure in the drug label.

Pharmacodynamics

There is limited information regarding Sotorasib Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Sotorasib Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Sotorasib Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Sotorasib Clinical Studies in the drug label.

How Supplied

There is limited information regarding Sotorasib How Supplied in the drug label.

Storage

There is limited information regarding Sotorasib Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Sotorasib Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Sotorasib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

LUMAKRAS

Look-Alike Drug Names

There is limited information regarding Sotorasib Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.