Imlunestrant

Imlunestrant is an antagonist and degrader of both wild-type and mutant oestrogen receptor alpha (ERα). In ER-positive breast cancer, oestrogen signalling through ERα drives the expression of genes that promote cell proliferation. By blocking the receptor and removing it from the cell, imlunestrant cuts this signal, and it keeps its activity against tumour models that carry ESR1 mutations.

Mechanism of Action

• Receptor binding and degradation: imlunestrant binds ERα with high affinity and, in vitro, induces its degradation.
• Effect on tumour cells: loss of the receptor inhibits ER-dependent gene transcription and cell proliferation in ER-positive breast cancer cells. Proliferation genes controlled by ERα include MYC and cyclin D1.
• Mutant receptor: antitumour activity has been shown in vitro and in vivo in ER-positive breast cancer models, including models with ESR1 mutations.
• Cardiac electrophysiology: across doses of 200 to 1,200 mg there was no effect of imlunestrant concentration on the QTc interval; at the Cmax of the 400 mg dose the mean change from baseline was 1.72 ms (90% CI −0.43 to 3.87).
• Clinical basis: efficacy and safety were evaluated in EMBER-3, an open-label phase 3 study in adults with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor, alone or with a CDK4/6 inhibitor.

Pharmacokinetics

• Absorption: absolute oral bioavailability is about 10.5% after a single 400 mg dose, and the median time to peak concentration is about 4 hours. At 400 mg once daily the steady-state Cmax is 141 ng/mL and the AUC0–24h is 2,400 ng·h/mL. Exposure rises in proportion to dose from 200 to 1,200 mg. Steady state is reached in about 6 days, with roughly 2.3-fold accumulation.
• Effect of food: a low-fat meal raised Cmax 3.55-fold and AUC 2.04-fold compared with fasting. The effect of a high-fat meal is unknown, so tablets are taken on an empty stomach.
• Distribution: apparent central volume of distribution about 4,310 L; plasma protein binding 99.93–99.96%.
• Metabolism: sulfation, CYP3A4 oxidation and direct glucuronidation. Imlunestrant is a P-glycoprotein substrate in vitro, but not a substrate of BCRP, OCT1, OATP1B1 or OATP1B3.
• Elimination: half-life about 30 hours; apparent clearance about 166 L/h. After a radiolabelled dose, 97.3% was recovered in faeces and 0.278% in urine.
• Special populations: age (28 to 95 years), race and body weight (36 to 145 kg) have no clinically meaningful effect. Mild hepatic impairment (Child-Pugh A) makes no relevant difference; unbound exposure (AUC) rose 1.82-fold in moderate (Child-Pugh B) and 2.33-fold in severe (Child-Pugh C) impairment. Exposure may be higher in severe renal impairment, end-stage renal disease and dialysis (limited data).

• Advanced breast cancer with an ESR1 mutation: monotherapy in adults with oestrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation, who have disease progression after prior treatment with an endocrine-based regimen.
• Combination with an LHRH agonist: in pre- or perimenopausal women, and in men, imlunestrant should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.
• Patient selection: the activating ESR1 mutation must be shown in tumour or plasma, using a CE-marked in vitro diagnostic test with the corresponding intended purpose. If none is available, an alternative validated test is used.

• Breastfeeding (lactation).
• Hypersensitivity to imlunestrant or to any of the excipients.

The most common and clinically relevant side effects are increased ALT (34.3%), increased AST (33.2%), fatigue (25.7%), diarrhoea (22.5%), nausea (20.1%) and vomiting (9.0%). The frequencies come from 378 patients who took 400 mg once daily in the EMBER-3 and EMBER studies. The only reaction that led more than one patient to stop treatment was increased ALT (0.8%).

Very common (≥1/10): diarrhoea, nausea, joint and muscle pain (arthralgia, myalgia and similar), back pain, fatigue, increased ALT, increased AST, increased triglycerides.

Common (≥1/100 to <1/10): decreased appetite, headache, venous thromboembolism, hot flush, cough, vomiting, constipation, abdominal pain.

Increases in ALT, AST and triglycerides are laboratory findings. Venous thromboembolism is the notable serious reaction in these groups, and liver enzyme rises are managed by interrupting, reducing or stopping the dose (see Administration and Dosage).

Imlunestrant is cleared by sulfation, CYP3A4 oxidation and glucuronidation. The SmPC reports these results:

• Strong CYP3A inducers: carbamazepine lowered imlunestrant AUC by 42% and Cmax by 29%. Avoid the combination; if it cannot be avoided, increase the imlunestrant dose by 200 mg once daily.
• Strong CYP3A inhibitors: itraconazole raised imlunestrant AUC 2.11-fold and Cmax 1.87-fold. Avoid the combination; if it cannot be avoided, decrease the imlunestrant dose by 200 mg once daily.
• Acid-reducing medicines: omeprazole had no clinically meaningful effect on imlunestrant exposure.
• P-glycoprotein inhibitors: quinidine had no clinically meaningful effect on imlunestrant.
• CYP2D6 substrates: dextromethorphan exposure rose by 1.33-fold (AUC) and 1.43-fold (Cmax). Use caution with CYP2D6 substrates for which a small rise in concentration can cause significant adverse events.
• P-gp substrates: digoxin exposure rose by 1.39-fold (AUC) and 1.60-fold (Cmax). Use the same caution.
• BCRP substrates: rosuvastatin exposure rose by 1.49-fold (AUC) and 1.65-fold (Cmax). Use the same caution.
• Food: food, even a low-fat meal, raises imlunestrant exposure; take the tablets fasted.

Treatment should be started and supervised by a physician experienced in anticancer therapy. Imlunestrant is taken by mouth at about the same time each day, on an empty stomach at least 2 hours before or 1 hour after food. The tablets are swallowed whole; they must not be split, crushed or chewed, because the effects have not been investigated. Exposure to the active substance could be harmful for caregivers.

Recommended Dose

• 400 mg once daily (two 200 mg tablets), continued for as long as the patient benefits or until unacceptable toxicity.
• In pre- or perimenopausal women and in men, an LHRH agonist is given alongside.

Dose Adjustments for Side Effects

• If a reduction is needed, the dose is lowered by 200 mg (to 200 mg once daily). Treatment is stopped in patients who cannot tolerate 200 mg once daily.
• Raised ALT or AST: monitor during treatment and as clinically indicated. Persistent or recurrent grade 2 (normal baseline): suspend until back to baseline or grade 1, no dose reduction. Grade 3 with a normal baseline, grade 2 or above with an abnormal baseline, or above 8 times the upper limit of normal: suspend until back to baseline or grade 1, then resume at 200 mg, or stop if already on 200 mg. Grade 4 with a normal baseline: stop. ALT or AST at least 3 times the upper limit with bilirubin at least 2 times the upper limit (or at least 2 times baseline with abnormal baseline), without cholestasis: stop.
• Other adverse reactions: persistent or recurrent grade 2 that does not settle within 7 days despite maximal supportive care: suspend until back to baseline or grade 1, no dose reduction. Grade 3 or 4 (except asymptomatic non-hepatic laboratory changes): suspend until back to baseline or grade 1, then resume at the next lower dose or stop if already on 200 mg. After grade 4, monitor closely on restarting.

With Strong CYP3A Inducers or Inhibitors

Avoid both. If unavoidable, increase the dose by 200 mg once daily with a strong inducer, or decrease it by 200 mg once daily with a strong inhibitor.

Special Populations

• Elderly: no adjustment for age; limited data in patients aged 75 years and over.
• Renal impairment: no adjustment in mild or moderate impairment. In severe impairment, end-stage renal disease or dialysis exposure may be higher; use with caution and watch closely for toxicity.
• Hepatic impairment: no adjustment in mild (Child-Pugh A) impairment; reduce to 200 mg once daily in moderate (Child-Pugh B) or severe (Child-Pugh C) impairment.
• Children and adolescents: there is no relevant use in the paediatric population for locally advanced breast cancer.

Missed or Vomited Dose

• Missed dose: it may be taken up to 6 hours after the usual time. After more than 6 hours, skip it for that day, do not take an extra dose, and take the next dose at the usual time the next day.
• Vomiting: do not take an extra dose that day; resume the usual schedule the next day.

ESR1 Mutation Testing

Treatment is for tumours with an activating ESR1 mutation, found in tumour tissue or plasma by a CE-marked test where one is available.

Taking the Tablets Fasted

Exposure is higher with food and the effect of a high-fat meal is unknown, so the dose is taken fasted (at least 2 hours before or 1 hour after food).

Liver Enzymes

Raised ALT and AST are the most common side effects. Liver tests are monitored during treatment and the dose is interrupted, reduced or stopped according to the thresholds above.

Handling by Caregivers

Exposure to the active substance could be harmful for caregivers; they should take care when handling the tablets.

Pregnancy, Breastfeeding and Fertility

• Before treatment: verify pregnancy status in females of reproductive potential.
• Contraception: females and males of reproductive potential should use highly effective contraception during treatment and for at least 1 week after the last dose.
• Pregnancy: there are no data in pregnant women, and imlunestrant can cause foetal harm. It should not be used during pregnancy or by women of childbearing potential who do not use contraception. If pregnancy occurs, the patient must be told of the hazard to the foetus and the risk of miscarriage.
• Breastfeeding: it is unknown whether imlunestrant or its metabolites pass into human milk; use during lactation is contraindicated.
• Fertility: animal findings and the mechanism of action suggest that fertility may be impaired in females and males of reproductive potential.

Sodium

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

Effect on Driving

Imlunestrant has no or negligible influence on the ability to drive and use machines. Patients who feel fatigued or weak should take care.

Inluriyo tablets need no special storage conditions. They are supplied in PCTFE/PVC blisters sealed with aluminium foil, in packs of 14, 28, 42, 56, 70 or 168 tablets (not all pack sizes may be marketed). Keep them out of the sight and reach of children.

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

Prescription only (Rx). The medicinal product is subject to special and restricted medical prescription (Annex II B) and is prescribed by a specialist experienced in cancer treatment. Imlunestrant is taken at home, so it is supplied to the patient or to the treating clinic on prescription.