LUMAKRAS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LUMAKRAS (LUMAKRAS).
KRAS G12C inhibitor that irreversibly and selectively binds to the cysteine-12 residue in the switch-II pocket, locking KRAS in an inactive GDP-bound state and inhibiting downstream signaling.
| Metabolism | Primarily metabolized by CYP3A4; minor contributions from CYP2C8, CYP2D6, and CYP3A5. |
| Excretion | Primarily hepatic metabolism; 88% in feces (53% as unchanged drug), 2% in urine (as metabolites). |
| Half-life | Terminal elimination half-life of 11 hours (range 5–15 hours), supporting twice-daily dosing. |
| Protein binding | 89–92% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution ~6.1 L/kg (range 4.2–8.5 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability approximately 10% (low due to extensive first-pass metabolism). |
| Onset of Action | Oral: clinical response observed within 2–4 weeks of starting therapy. |
| Duration of Action | Duration of action corresponds to dosing interval of every 12 hours; continuous daily dosing required for sustained effect. |
960 mg orally once daily on an empty stomach (no food for at least 2 hours before and 1 hour after dose).
| Dosage form | TABLET |
| Renal impairment | For GFR ≥30 mL/min: no adjustment. For GFR <30 mL/min: not recommended (no data). |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce to 480 mg once daily. Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients (no data). |
| Geriatric use | No specific dose adjustment recommended; monitor for adverse events due to potential age-related renal/hepatic decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LUMAKRAS (LUMAKRAS).
| Breastfeeding | There are no data on the presence of sotorasib in human milk, its effects on the breastfed infant, or its effects on milk production. Due to the potential for serious adverse reactions in breastfed infants from sotorasib, advise women not to breastfeed during treatment and for at least 1 week after the last dose. The M/P ratio is unknown. |
| Teratogenic Risk | Based on its mechanism of action (KRAS G12C inhibitor) and animal studies, LUMAKRAS (sotorasib) is expected to cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of sotorasib to pregnant rats during organogenesis at exposures approximately 2.6 times the human exposure at the recommended dose resulted in embryofetal mortality, reduced fetal body weight, and skeletal variations. There are no adequate and well-controlled studies in pregnant women. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. For the first trimester, there is a high risk of teratogenicity; for the second and third trimesters, there is a risk of fetal growth impairment and adverse developmental outcomes. |
■ FDA Black Box Warning
None.
| Serious Effects |
None.
| Precautions | ["Interstitial lung disease (ILD)/pneumonitis: Monitor for new or worsening pulmonary symptoms; withhold, dose reduce, or permanently discontinue based on severity.","Hepatotoxicity: Monitor liver function tests before and during treatment; withhold, dose reduce, or permanently discontinue based on severity."] |
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| Fetal Monitoring | Monitor pregnant women exposed to LUMAKRAS for fetal growth and development via serial ultrasound assessments. If a woman becomes pregnant during treatment, immediately assess for potential fetal harm. Monitor liver function tests monthly during treatment as sotorasib can cause hepatotoxicity. Also monitor for interstitial lung disease/pneumonitis, which may present as acute respiratory distress. For women of reproductive potential, perform pregnancy testing prior to initiating treatment. |
| Fertility Effects | Based on animal studies, sotorasib may impair fertility in females. In a fertility study in female rats, sotorasib caused a decrease in the number of corpora lutea and implantation sites, decreased fertility index, and increased pre-implantation loss at exposures approximately 2.6 times the human exposure. The effects on human fertility are unknown. Reversibility of these effects is not established. |