Sotorasib

Sotorasib is a selective inhibitor of the mutant KRAS G12C protein. KRAS is a small GTP-binding protein that switches between an active GTP-bound state and an inactive GDP-bound state, and while active it passes growth signals on through the MAP kinase pathway. The G12C mutation impairs the breakdown of GTP, so the protein stays switched on. Sotorasib targets a cysteine that is present in the mutant protein but absent from normal (wild-type) KRAS.

Mechanism of Action

• Covalent, irreversible binding: sotorasib binds covalently and irreversibly to the unique cysteine of KRAS G12C and holds the protein in its inactive state.
• Selectivity: because the target cysteine is not present in wild-type KRAS, the effect is limited to tumours that harbour KRAS G12C. The mutation is found in roughly 13% of non-small cell lung cancers.
• Cellular effect: inactivating KRAS G12C blocks tumour cell signalling and survival, inhibits cell growth and promotes apoptosis (programmed cell death) in these tumours.

Pharmacokinetics

• Absorption: bioavailability has not been studied in humans. After an oral dose, the median time to peak concentration is 1–2 hours. A high-fat, high-calorie meal did not change the peak concentration and raised AUC by 38%, so the tablets can be taken with or without food.
• Dose and exposure: pharmacokinetics are non-linear; peak concentration and AUC rise less than in proportion to dose over 180–960 mg once daily. After 8 daily doses, 240 mg gave peak concentration and AUC about 22% lower than 960 mg, and average values after repeated doses were similar across all regimens from 180 to 960 mg once daily.
• Distribution: the apparent volume of distribution is about 211 L. Plasma protein binding in vivo is 97.6%, and sotorasib binds preferentially to alpha-1-acid glycoprotein in vitro.
• Metabolism: the main pathways are non-enzymatic conjugation and oxidative metabolism. In vitro, CYP2C8, CYP3A4 and CYP3A5 are involved, and sotorasib is a P-gp substrate. The main circulating metabolites (a cysteine adduct and an oxidative metabolite formed by CYP3A) are not pharmacologically active.
• Elimination: apparent clearance is about 26.2 L/h and the mean half-life about 5 hours. Steady state is reached within 22 days. About 74% of a dose is recovered in faeces and 6% in urine (1% as unchanged drug).
• Special populations: no dose adjustment is needed in mild hepatic or mild renal impairment; data are lacking in moderate and severe impairment (see Administration and Dosage).

• Advanced non-small cell lung cancer (NSCLC) with a KRAS G12C mutation: as monotherapy in adults whose disease has progressed after at least one prior line of systemic therapy.
• The KRAS G12C mutation must be confirmed with a validated test before treatment starts.

• Hypersensitivity to sotorasib or to any of the excipients.

The adverse reactions below reflect 740 patients with KRAS G12C-mutated solid tumours who received sotorasib 960 mg once daily as monotherapy (median exposure 4.2 months). The most common were diarrhoea (36.6%), nausea (24.7%), fatigue (19.1%), vomiting (16.1%), arthralgia (15.3%) and decreased appetite (15.1%). The most common severe (grade 3 or higher) reactions were diarrhoea (6.9%), increased alanine aminotransferase (5.9%) and increased aspartate aminotransferase (4.6%). The reactions that most often led to permanent discontinuation were increased ALT (1.5%), increased AST (1.1%) and drug-induced liver injury (1%), and those that most often led to dose modification were diarrhoea (11.4%), increased ALT (5.9%), increased AST (5.7%), nausea (3.8%), increased alkaline phosphatase (2.4%) and vomiting (2%).

Very common (≥1/10): anaemia, cough, dyspnoea, diarrhoea, nausea, vomiting, constipation, abdominal pain (upper, lower or unspecified), arthralgia, back pain, fatigue, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite.

Common (≥1/100 to <1/10): headache, interstitial lung disease or pneumonitis, drug-induced liver injury, pyrexia, increased blood alkaline phosphatase, increased blood bilirubin, increased gamma-glutamyltransferase, hypokalaemia.

Uncommon (≥1/1,000 to <1/100): hepatitis, renal impairment, renal failure, chronic kidney disease, acute kidney injury.

Hepatotoxicity and interstitial lung disease or pneumonitis are the important serious reactions. Pneumonitis can be fatal, and rises in liver enzymes can occur without symptoms (see Special Instructions).

Sotorasib is metabolised by CYP2C8, CYP3A4 and CYP3A5 and is a P-gp substrate. It is also a moderate CYP3A4 inducer, a weak BCRP inhibitor and, in vitro, an inhibitor of CYP2D6, so it can change the levels of other medicines.

• Acid-reducing agents (proton pump inhibitors and H2 receptor antagonists): they lower sotorasib levels and efficacy may be reduced. With a meal, omeprazole reduced peak concentration by 65% and AUC by 57%, and famotidine (given 10 hours before and 2 hours after sotorasib) by 35% and 38%. If an acid-reducing agent is required, Lumykras should be taken with an acidic beverage such as cola; alternatively, take it 4 hours before or 10 hours after a local antacid.
• CYP3A4 inhibitors: itraconazole, a strong CYP3A4 and P-gp inhibitor, did not raise sotorasib exposure to a clinically significant extent, so no dose adjustment is recommended.
• Strong CYP3A4 inducers (rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin, St John’s wort): not recommended, because they may lower sotorasib exposure. Rifampicin reduced peak concentration by 35% and AUC by 51%.
• CYP3A4 substrates: sotorasib lowers their levels and may reduce their efficacy; a sensitive CYP3A4 probe substrate fell by about half (peak 48%, AUC 53%). Combination should be avoided with CYP3A4 substrates that have a narrow therapeutic index, including alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus, tacrolimus, amlodipine and manidipine. If it cannot be avoided, the dose of the substrate is adjusted according to its own SmPC.
• CYP2B6, CYP2C8, CYP2C9 and CYP2C19 substrates: sotorasib may induce these enzymes in vitro; the clinical relevance is unknown and appropriate monitoring is recommended.
• CYP2D6 substrates (for example flecainide, propafenone, metoprolol): sotorasib may inhibit CYP2D6 in vitro; the clinical relevance is unknown and appropriate monitoring is recommended.
• BCRP substrates (lapatinib, methotrexate, mitoxantrone, rosuvastatin, topotecan): sotorasib raises their levels (rosuvastatin peak concentration by 70% and AUC by 34%). Monitor for side effects and reduce the substrate dose according to its own SmPC.
• P-gp substrates: digoxin peak concentration rose 1.9-fold and AUC 1.2-fold. Combination with P-gp substrates that have a narrow therapeutic index is not recommended; if it cannot be avoided, the substrate dose is adjusted according to its own SmPC.
• Hormonal contraceptives: effectiveness may be reduced; a barrier method should be added (see Special Instructions).
• Food: Lumykras can be taken with or without food.

Treatment must be started by a physician experienced in the use of anticancer medicines, and the presence of a KRAS G12C mutation must first be confirmed with a validated test. The tablets are swallowed whole, with or without food, at the same time each day. There are no data to support chewing, crushing or splitting them, but they can be dispersed in water (see below).

Recommended Dose

• 960 mg once daily: eight 120 mg tablets or four 240 mg tablets.
• Treatment continues until disease progression or unacceptable toxicity.

Dose Reduction Levels

• Starting dose: 960 mg once daily.
• First reduction: 480 mg once daily (four 120 mg tablets or two 240 mg tablets).
• Second reduction: 240 mg once daily (two 120 mg tablets or one 240 mg tablet).
• At most two dose reductions are recommended. Treatment is stopped if a reaction cannot be managed after two reductions and the patient cannot tolerate 240 mg once daily.

Dose Modifications for Side Effects

• Hepatotoxicity, AST or ALT above 3 and up to 5 times the upper limit of normal (ULN) with symptoms, or above 5 times the ULN without another cause: withhold treatment and monitor liver function closely until values recover to 3 times the ULN or less (or to 3 times baseline or less if baseline was abnormal); then resume at the next lower dose level. Corticosteroids may be considered.
• Hepatotoxicity, AST or ALT above 3 times the ULN with total bilirubin above 2 times the ULN, or with INR above 1.5 times the ULN in patients not on anticoagulants, without another cause: stop permanently if no alternative cause is found. If an alternative cause is identified, do not resume until AST, ALT and bilirubin return to baseline.
• Interstitial lung disease or pneumonitis (any grade): stop treatment if suspected, and stop permanently if confirmed and no other cause is found.
• Nausea, vomiting or diarrhoea of grade 3 or higher that persists despite supportive care (including anti-emetic or anti-diarrhoeal treatment): stop until recovery to grade 1 or baseline, then resume at the next lower dose level.
• Other medicine-related toxicity of grade 3 or higher: stop until recovery to grade 1 or baseline, then resume at the next lower dose level.

Special Populations

• Elderly: limited data in patients aged 75 years and older do not suggest that a dose adjustment is needed.
• Hepatic impairment: no adjustment in mild impairment; use is not recommended in moderate (Child-Pugh B) or severe (Child-Pugh C) impairment.
• Renal impairment: no adjustment in mild impairment (creatinine clearance 60 mL/min or more); not studied in moderate or severe impairment, so caution is needed in moderate, severe and end-stage renal impairment.
• Children and adolescents: no relevant use in non-small cell lung cancer.

Missed or Vomited Dose

If less than 6 hours have passed since the scheduled time, the dose is taken as usual. If more than 6 hours have passed, the dose is not taken and treatment continues the next day. After vomiting, no extra dose is taken that day; treatment continues the next day.

Patients Who Have Difficulty Swallowing

• Disperse the tablets, without crushing them, in 120 mL of non-carbonated water at room temperature; no other liquid may be used. Stir until the tablets break into small pieces (they do not dissolve completely) and drink immediately. The mixture may look pale to bright yellow.
• Rinse the container with another 120 mL of water and drink it immediately. If not drunk at once, stir again; discard the dispersion if it is not drunk within 2 hours.
• For a nasogastric or gastrostomy (PEG) tube, prepare the dispersion and rinse in the same way and give them according to the tube manufacturer’s instructions with water flushes, within 2 hours of preparation and stored at room temperature.

KRAS G12C Testing

A KRAS G12C mutation must be confirmed with a validated test before Lumykras is started.

Hepatotoxicity

Sotorasib can cause liver injury, including drug-induced liver injury and hepatitis, with transient rises in ALT, AST, alkaline phosphatase and total bilirubin. Of 740 patients on 960 mg daily, 26% had hepatotoxicity and 13% needed a dose interruption or reduction. It was most frequent in patients whose last immunotherapy was within 3 months (38%), compared with 17% when it was more than 3 months earlier and 22% with no prior immunotherapy. In 87% of cases the rise improved or resolved with interruption and corticosteroids, and enzyme rises can be symptom-free. Liver function (ALT, AST, alkaline phosphatase, total bilirubin) is checked before starting, every 3 weeks for the first 3 months, then monthly or as clinically indicated, and more often after recent immunotherapy or a serious liver event.

Interstitial Lung Disease and Pneumonitis

Interstitial lung disease or pneumonitis can occur and can be fatal. It occurred in patients with earlier immunotherapy or radiotherapy, and immunotherapy within the last 3 months may be a risk factor. Patients are monitored for new or worsening breathing symptoms (shortness of breath, cough, fever). Lumykras is withheld immediately if it is suspected and stopped permanently if no other cause is found.

Hepatic Impairment

There are no data on repeated doses in moderate or severe hepatic impairment (Child-Pugh B and C), so no dose recommendation can be made.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: women of childbearing potential must avoid pregnancy and use highly effective contraception during treatment and for at least 7 days after the last dose. Sotorasib may reduce the effectiveness of hormonal contraceptives, so women using them should add a barrier method.
• Pregnancy: there are no data in pregnant women and animal studies showed reproductive toxicity. Lumykras is not recommended in pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: it is unknown whether sotorasib passes into human milk and a risk to the infant cannot be excluded, so it should not be used while breastfeeding.
• Fertility: no clinical studies have looked at the effect on fertility.

Lactose

Each 120 mg tablet contains 114 mg and each 240 mg tablet 53 mg of lactose (as monohydrate). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it.

Sodium

Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Lumykras has no or negligible influence on the ability to drive and use machines.

Lumykras tablets need no special storage conditions. They are supplied in blisters or, for the 120 mg strength, in plastic bottles with a child-resistant cap. Keep them in the original pack, out of the sight and reach of children. A dispersion of tablets in water must be taken within 2 hours.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B), on the prescription of a physician experienced in the use of anticancer medicines. Lumykras is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.