Inluriyo 200 mg film-coated tablets

Inluriyo is indicated as monotherapy for the treatment of adult patients with oestrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1-mutation, who have disease progression following prior treatment with an endocrine based regimen (for biomarker-based patient selection, see section 4.2).

In pre- or perimenopausal women, or men, Inluriyo should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

Treatment should be initiated and supervised by a physician experienced in the use of anticancer therapies.

Patient selection

Patients with ER-positive, HER2-negative advanced breast cancer should be selected for treatment based on the presence of an activating ESR1-mutation in tumour or in plasma specimens, using a CE-marked in vitro diagnostic (IVD) with the corresponding intended purpose. If the CE-marked IVD is not available, the presence of an activating ESR1-mutation should be assessed by an alternative validated test.

Posology

The recommended dose of imlunestrant is 400 mg orally (two 200 mg film-coated tablets), once daily.

It is recommended that treatment is continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.

Missed dose

If a dose is missed, it can be taken up to 6 hours after the time it is usually taken. After more than 6 hours, the dose should be skipped for that day. An additional dose should not be taken. On the next day, the dose should be taken at the usual time.

Vomiting

If the patient vomits after taking the dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time.

Dose adjustments

If dose reduction is necessary, the dose should be decreased by 200 mg. Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Tables 1 and 2. The treatment should be discontinued for patients unable to tolerate 200 mg once daily.

Table 1: Recommended dose modification for increased ALT and AST

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be monitored during treatment, and as clinically indicated.

^aNCI CTCAE v5.0

ULN: upper limit of normal

Table 2: Recommended dose modification for adverse reactions (except increased ALT and AST)

^a NCI CTCAE 5.0

Strong CYP3A inducers

Concomitant use of strong CYP3A inducers should be avoided. If strong CYP3A inducers cannot be avoided, the imlunestrant dose should be increased by 200 mg once daily (see section 4.5).

Strong CYP3A inhibitors

Concomitant use of strong CYP3A inhibitors should be avoided. If strong CYP3A inhibitors cannot be avoided, the imlunestrant dose should be decreased by 200 mg once daily (see section 4.5).

Special populations

Elderly

No dose adjustment is required on the basis of patient age (see section 5.2). Limited data are available in patients ≥ 75 years of age (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A).

The dose should be reduced to 200 mg once daily in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Renal impairment

No dose adjustment is necessary in patients with mild or moderate renal impairment. Limited data indicates that the exposure of imlunestrant may be increased in patients with severe renal impairment, end stage renal disease, or in patients on dialysis (see section 5.2). Treatment should be administered with caution in patients with severe renal impairment, with close monitoring for signs of toxicity.

Paediatric population

There is no relevant use of imlunestrant in the paediatric population in the indication of locally advanced breast cancer.

Method of administration

Inluriyo is for oral use.

Patients should take their dose at approximately the same time each day.

The tablets should be taken on an empty stomach at least 2 hours before or 1 hour after food (see section 5.2). The tablets should be swallowed whole (patients should not split, crush, or chew the tablets before swallowing). The effects of splitting, crushing, or chewing the tablets have not been investigated and may impact the safety, efficacy, or stability of the product. Exposure to the active substance could be harmful for caregivers.

Lactation (see section 4.6).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Food effect

Imlunestrant exposures in the presence of a high-fat meal are unknown. The dose should be taken in the fasted state as higher exposures may occur with food.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”.

Imlunestrant is metabolized by sulfation, CYP3A4 oxidation and direct glucuronidation.

Potential for other medicinal products to effect imlunestrant

Strong CYP3A inducers

Coadministration of imlunestrant with carbamazepine (a strong CYP3A inducer) decreased the area under the concentration-time curve (AUC) and maximum concentration (C_max) of imlunestrant by 42 % and 29 %, respectively. Concomitant use of strong CYP3A inducers should be avoided. If strong CYP3A inducers cannot be avoided, the imlunestrant dose should be increased by 200 mg once daily (see section 4.2).

Strong CYP3A inhibitors

Coadministration of imlunestrant with itraconazole (a strong CYP3A inhibitor) increased the AUC and C_max of imlunestrant by 2.11-fold and 1.87-fold, respectively. Concomitant use of strong CYP3A inhibitors should be avoided. If strong CYP3A inhibitors cannot be avoided, the imlunestrant dose should be decreased by 200 mg once daily (see section 4.2).

Gastric acid reducing agents

Coadministration of imlunestrant with omeprazole (a proton pump inhibitor) had no clinically meaningful effect on the pharmacokinetics of imlunestrant.

Potential for imlunestrant to effect other medicinal products

CYP2D6 substrates

Imlunestrant increased the AUC and C_max of dextromethorphan (a CYP2D6 substrate) by 1.33-fold and 1.43-fold, respectively. Caution should be used when coadministering imlunestrant with CYP2D6 substrates for which a small increase in concentration leads to significant adverse events.

P-glycoprotein (P-gp) substrates

Imlunestrant increased the AUC and C_max of digoxin (a P-gp substrate) by 1.39-fold and 1.60-fold, respectively. Caution should be used when coadministering imlunestrant with P-gp substrates for which a small increase in concentration leads to significant adverse events.

BCRP substrates

Imlunestrant increased the AUC and C_max of rosuvastatin (a BCRP substrate) by 1.49-fold and 1.65-fold, respectively. Caution should be used when coadministering imlunestrant with BCRP substrates for which a small increase in concentration leads to significant adverse events.

Women of childbearing potential/Contraception in males and females

The pregnancy status of females of reproductive potential should be verified prior to starting treatment.

Females and males of reproductive potential should be advised to use highly effective contraception during treatment and for at least 1 week after the last dose (see section 5.3).

Pregnancy

There are no data from the use of imlunestrant in pregnant women. Based on the mechanism of action of imlunestrant and findings from embryofoetal toxicity studies in animals, imlunestrant can cause foetal harm when administered to pregnant women (see section 5.3). Imlunestrant should not be used during pregnancy and in women of childbearing potential not using contraception. If pregnancy occurs during treatment, the patient must be informed of the potential hazard to the foetus and potential risk of miscarriage.

Breast-feeding

It is unknown whether imlunestrant or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in the breast-fed infant, use during lactation is contraindicated (see section 4.3).

Fertility

Based on findings from animal studies (see section 5.3) and its mechanism of action, imlunestrant may impair fertility in females and males of reproductive potential.

Imlunestrant has no or negligible influence on the ability to drive and use machines. However, since fatigue and asthenia have been reported with imlunestrant, caution should be observed by those patients who experience this adverse reaction when driving or operating machinery.

Summary of the safety profile

The most common and clinically relevant adverse reactions were ALT increased (34.3 %), AST increased (33.2 %), fatigue (25.7 %), diarrhoea (22.5 %), nausea (20.1 %), and vomiting (9.0 %).

Adverse reactions leading to discontinuations of treatment in more than 1 patient included ALT increased (0.8 %) only.

Tabulated list of adverse reactions

The frequencies of adverse drug reactions (ADRs) displayed below are based on pooled data in 378 patients, treated with 400 mg imlunestrant once daily from a randomised, open-label, multicenter Phase 3 study (EMBER-3) and an open-label, multicenter, dose escalation and dose expansion phase 1a/1b study (EMBER).

In the following tables, adverse reactions are listed in order of MedDRA body system organ class and frequency. Frequency gradings are: very common (≥ 1 / 10), common (≥ 1 / 100 to < 1 / 10), uncommon (≥ 1 / 1 000 to < 1 / 100), rare (≥ 1 / 10 000 to < 1 / 1 000), very rare (< 1 / 10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions in patients receiving imlunestrant

^a Consolidated term consisting of analogous preferred terms.

^b Consolidated term consisting of preferred terms: arthralgia, myalgia, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, pain in extremity, neck pain.

^c Based on laboratory assessments.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms of overdose have not been established. The ADRs reported in association with doses higher than the recommended dose were consistent with the established safety profile (see section 4.8). The most frequent ADRs at higher doses were diarrhoea, nausea, fatigue and arthralgia. There is no known antidote for an overdose of imlunestrant. Patients should be closely monitored, and supportive care should be provided.

Pharmacotherapeutic group: Not yet assigned, ATC code: Not yet assigned.

Mechanism of action

Imlunestrant is an antagonist and degrader of wild-type and mutant oestrogen receptor-α (ERα), leading to inhibition of oestrogen receptor-dependent gene transcription and cellular proliferation in ER-positive breast cancer cells.

Pharmacodynamic effects

Cardiac electrophysiology

The effect of imlunestrant monotherapy on the QTc interval was evaluated in 79 patients with matching pharmacokinetics and QTcF samples from EMBER. Results showed no effect of imlunestrant concentrations across the 200 mg to 1 200 mg dose range on QTc interval, with the upper bound of the 90 % CI of the mean delta QTc less than 10 ms at C_max of 400 mg (change from baseline of 1.72 ms; 90 % CI: -0.43, 3.87).

Clinical efficacy and safety

The efficacy and safety of imlunestrant was evaluated in EMBER 3, a Phase 3 global, randomized, open-label study for adult patients with ER-positive, HER2-negative, locally advanced (not amenable to curative treatment by surgery) or metastatic breast cancer (mBC), who have been treated with an aromatase inhibitor (AI), alone or in combination with a CDK4/6 inhibitor.

Eligible patients were pre-, peri- and postmenopausal women, or men, (≥ 18 years of age) with ER-positive, HER2-negative advanced breast cancer that had previously received an AI alone or combined with a CDK4/6 inhibitor in the adjuvant or metastatic setting. Patients had either: experienced recurrence while receiving or within 12 months of completing adjuvant treatment with an AI alone or with a CDK4/6 inhibitor for early breast cancer, experienced recurrence > 12 months after completing adjuvant treatment followed by disease progression on or after an AI alone or with a CDK4/6 inhibitor, or been diagnosed with de novo metastatic disease and had disease progression on or after an AI alone or with a CDK4/6 inhibitor. All patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function, and evaluable lesions per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, i.e., measurable disease or bone only disease with evaluable lesions. LHRH agonists were given to pre- and perimenopausal women, and men. Patients with presence of symptomatic metastatic visceral disease, and patients with cardiac comorbidity were excluded.

Patients were enrolled regardless of ESR1-mutation status. ESR1-mutational status was determined by blood circulating tumour deoxyribonucleic acid (ctDNA) using the Guardant360 CDx assay. A result was considered ESR1-positive if at least one of 34 predefined ESR1 variants was detected: E380A, E380D, E380K, E380Q, E380V, M421_V422delinsl, V422_E423del, V422del, S463F, S463P, L469V, L536F, L536G, L536H, L536I, L536K, L536N, L536P, L536Q, L536R, L536V, Y537C, Y537D, Y537G, Y537H, Y537N, Y537P, Y537Q, Y537S, D538E, D538G, D538H, D538N, D538V. Among these, 17 variants were identified within the EMBER-3 study population: E380K, E380Q, V422del, S463P, L469V, L536H, L536K, L536P, L536Q, L536R, Y537C, Y537D, Y537N, Y537S, D538E, D538G, D538N.

A total of 874 patients were randomised 1:1:1 between 3 treatment arms: 400 mg oral daily administration of Inluriyo (Arm A), investigators choice of standard of care (SOC) (fulvestrant or exemestane) (Arm B), or 400 mg oral daily administration of Inluriyo in combination with abemaciclib (Arm C). Among the 330 patients randomised to investigators choice endocrine therapy (Arm B), 292 received fulvestrant (90 %), and 32 received exemestane (10 %). Randomization was stratified by previous treatment with CDK4/6 inhibitor (yes vs. no), presence of visceral metastasis (yes vs. no), and region (East Asia vs. North America/Western Europe vs. Others). The demographics and baseline disease characteristics were well balanced between treatment arms. Baseline demographics of the overall study population were as follows: median age was 61 years (range: 27 - 89) and 13 % were ≥ 75 years, 99 % were female, 56 % were white, 30 % Asian, 3 % Black, and 11 % were other or missing. The majority of patients were treated in the second-line advanced setting (67 %) versus the first-line setting (33 %), and the majority had received a prior CDK4/6i (60 %), 37 % received palbociclib, 15 % ribociclib and 3 % abemaciclib. Baseline ECOG performance was 0 (65 %) or 1 (35 %). Patient demographics for those with ESR1-mutated tumours were generally representative of the broader study population.

The primary efficacy endpoint was progression-free survival (PFS) as assessed by investigator. Key secondary endpoint for EMBER-3 was overall survival (OS).

EMBER 3: Inluriyo monotherapy for patients with ESR1m

At the primary analysis (24 June 2024 cut-off), a statistically significant improvement in PFS was observed in patients who received Inluriyo monotherapy versus SOC in the ESR1m subpopulation. The comparison of Inluriyo monotherapy versus SOC was not statistically significant in the ITT population. Efficacy results in the ESR1m subpopulation are provided in Table 4 and Figure 1.

Table 4: Summary of efficacy data for patients with ESR1m treated with Inluriyo monotherapy in EMBER-3

CI=confidence interval; ESR1 = oestrogen receptor 1.

* Kaplan-Meier estimate; 95 % CI based on the Brookmeyer-Crowley method.

** From a Cox proportional hazards model and a stratified log-rank test stratified by previous treatment with CDK4/6 inhibitor (yes vs. no) and presence of visceral metastasis (yes vs. no).

Data cut-off date 24 June 2024

Figure 1: Kaplan-Meier Curve of progression free survival for patients with ESR1m treated with Inluriyo monotherapy in EMBER-3

In the CDK4/6i naïve subgroup, the median PFS in the Inluriyo arm was 11.1 months (95 % CI: 5.5, 16.5) compared to 5.7 months (95 % CI: 3.8, 7.4) in SOC arm (HR = 0.42; 95 % CI: 0.25, 0.72). In the CDK4/6i pre-treated subgroup, the median PFS in the Inluriyo arm was 3.9 months (95 % CI: 2.0, 6.0) compared to 3.7 months (95 % CI: 2.2, 4.6) in SOC arm (HR = 0.72; 95 % CI: 0.52, 1.0).

At the third OS interim analysis (18 August 2025 cut-off), 128 events were observed across the two arms, and the HR was 0.60 (95 % CI: 0.43, 0.86).

Paediatric population

The licensing authority has waived the obligation to submit the results of studies with imlunestrant in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).

In a population pharmacokinetic analysis, the steady-state mean (CV %) maximum concentration (C_max) of imlunestrant is 141 ng/mL (45 %) and the AUC_0-24h is 2 400 ng*h/mL (46 %) after administration of the recommended dose of 400 mg once daily. The C_max and AUC of imlunestrant increase proportionally over a dose range from 200 mg to 1 200 mg once daily (0.5 to 3 times the approved recommended dose).

Absorption

The mean (CV %) absolute bioavailability of imlunestrant after a single oral 400 mg dose is 10.5 % (32 %). The median time to reach peak plasma concentration (t_max) is approximately 4 hours.

Effect of food

Administration of imlunestrant 400 mg with a low-fat meal (approximately 400 - 500 calories with 100 - 125 calories from fat) increased C_max by 3.55-fold and AUC_(0-∞) by 2.04-fold compared to fasted administration. Imlunestrant exposures in the presence of a high-fat meal are unknown.

Distribution

In a population pharmacokinetic analysis, the mean (CV %) apparent central volume of distribution of imlunestrant is 4 310 L (69 %) in patients with advanced or metastatic breast cancer. Human protein binding of imlunestrant is 99.93 % to 99.96 % at clinically relevant concentrations.

Biotransformation

Imlunestrant is metabolized by sulfation, CYP3A4 oxidation and direct glucuronidation.

In vitro studies indicated that imlunestrant is a substrate of P-gp but not a substrate of BCRP, OCT1, OATP1B1, or OATP1B3.

Coadministration of imlunestrant with quinidine (P-gp inhibitor) had no clinically meaningful effect on the pharmacokinetics of imlunestrant.

Elimination

The elimination half-life of imlunestrant is approximately 30 hours and the mean (CV %) apparent clearance is 166 L/h (51 %). Following a single radiolabelled dose of imlunestrant 400 mg to healthy subjects, 97.3 % of the dose was recovered in feces and 0.278 % in urine.

Special populations

Effect of age, race, and body weight

In a population pharmacokinetic analysis, age (range: 28 years to 95 years), race and body weight (range: 36 kg to 145 kg) had no clinically meaningful effect on the pharmacokinetics of imlunestrant.

Hepatic impairment

There were no clinically relevant differences in the pharmacokinetics of imlunestrant in subjects with mild hepatic impairment (Child-Pugh A). The AUC of unbound imlunestrant increased 1.82-fold in subjects with moderate hepatic impairment (Child-Pugh B) and 2.33-fold in subjects with severe hepatic impairment (Child-Pugh C).

Renal impairment

In a population pharmacokinetic analysis, mild renal impairment (60 mL/min ≤ eGFR < 90 mL/min) and moderate renal impairment (30 mL/min ≤ eGFR < 60 mL/min) had no effect on the exposure of imlunestrant. The effect of severe renal impairment (15 mL/min ≤ eGFR < 30 mL/min) suggested exposure could be increased based on limited data in 2 trial participants. Pharmacokinetics of imlunestrant in patients on dialysis is unknown.

Repeat-dose toxicity

Repeat-dose studies were conducted in rats and non-human primates to characterize toxicity. Adverse reactions observed at clinically relevant exposure levels were ovarian cysts and marked increases in ovarian weights, atrophy of the endometrium and myometrium of the uterus, epithelium and stroma of the cervix, and epithelium of the vagina in non-human primates. Minor, non-adverse vacuolation of macrophages in the mesenteric lymph node and ileum of non-human primates occurred at exposures that were 0.8-times and 11-times greater than human exposure (AUC_0-24) at 400 mg. Similar effects were observed in rats at exposures 4-times greater than human exposure (AUC_0-24) at 400 mg. Other important effects in rats were hyperplasia of the urinary bladder transitional epithelium, minimal to mild renal tubular degeneration, minimal inflammation of the renal pelvis, minimal to mild ocular lens fibre degeneration, non-adverse hypertrophy of the pituitary pars distalis in females, non-adverse decrease in pituitary gland weights, and non-adverse atrophy or hypertrophy of the adrenal cortex, which occurred at exposures at least 4-times greater than human exposure (AUC_0-24) at 400 mg.

Genotoxicity

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity potential.

Reproductive and developmental toxicity

Based on findings in animals and its mechanism of action, imlunestrant may cause effects on male and female fertility which were generally reversible, and fetal harm when administered during pregnancy. Ovarian cysts and atrophy of the vagina, cervix, or uterus were observed in rats at and monkeys, at exposures that were 4-fold and 0.8-fold higher, respectively, than human exposure (AUC_0-24) at 400 mg. Additional reproductive findings occurred in rats and consisted of cessation of estrous cycling, lobular hyperplasia or hypertrophy of the female mammary gland epithelium, spermatid retention, and cellular debris in the lumen of the epididymis at exposures (AUC_0-24) at least 4-fold above that in humans. Administration of imlunestrant to pregnant rats during the period of organogenesis led to maternal toxicity, early delivery, embryo lethality, and teratogenic fetal effects at maternal exposures less than or equal to human therapeutic exposure.

Carcinogenicity

In the 26-week transgenic mouse carcinogenicity study, rasH2 mice were given oral doses of 5, 375, or 750 mg/kg imlunestrant, which caused an increased incidence of benign and malignant sex cord stromal tumours (granulosa and mixed cell) in the ovaries of mice at all dose levels. These doses correspond to 2-, 32-, and 41-times the human AUC at the recommended dose. Induction of such tumours is consistent with the pharmacology-related endocrine feedback alterations in gonadotropin levels caused by an anti-oestrogen.

Tablet core

Croscarmellose sodium (E 468)

Hydroxypropylcellulose (E 463)

Magnesium stearate (E 470b)

Cellulose, microcrystalline (E 460)

Film-coating

Macrogols (E 1521)

Poly (vinyl alcohol) (E 1203)

Talc (E 553b)

Titanium dioxide (E 171)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Polychlorotrifluoroethylene (PCTFE) / Polyvinylchloride (PVC) blister sealed with aluminium foil in packs of 28 or 56 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.