INLURIYO Film-coated tablet Ref.[116183] Active ingredients: Imlunestrant

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 European Medicines Agency 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).