Abstract
The estrogen receptor (ER) is the key therapeutic target for ER‐positive (ER+) breast cancer. Novel ER degraders may overcome resistance to available endocrine therapy while providing consistent oral bioavailability. Imlunestrant is a novel, orally bioavailable selective estrogen receptor degrader (SERD) designed to deliver continuous ER target inhibition. A phase 1, open‐label, 3‐site study was conducted to characterize the pharmacokinetic (PK) profile of imlunestrant in individuals with varying degrees of hepatic impairment based on Child‐Pugh and National Cancer Institute classifications. In this study, participants received a single oral dose of imlunestrant at either 200 or 400 mg in the fasted state, and the pharmacokinetics and safety were assessed in individuals with normal hepatic function and those with mild, moderate, or severe hepatic impairment. Based on Child‐Pugh classification, there were no significant differences in the exposure profiles of imlunestrant in participants with mild hepatic impairment in comparison to participants with normal hepatic function. In participants with moderate and severe hepatic impairment, there were significant increases in imlunestrant AUC (but not Cmax) observed when compared with normal hepatic function (by 120% and 191% for AUC(0‐tlast) and 122% and 206% for AUC(0‐∞), respectively). Most treatment‐emergent adverse events (TEAEs) were mild or moderate in severity. Nausea and headache were the only TEAEs reported by more than one participant. Treatment‐related adverse events were reported by two participants, one each from the moderate and severe hepatic impairment groups. This data will inform the recommendations for dosing patients with hepatic impairment under treatment with imlunestrant.
Keywords: breast cancer, hepatic impairment, imlunestrant, pharmacokinetics, SERD
Introduction
Breast cancer is the most common cancer affecting women and is a leading cause of cancer‐related deaths worldwide. In 2022, it was estimated that over 2 million new cases of breast cancer were diagnosed in women globally. 1 Treatment options for women with breast cancer are largely determined by tumor hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. 2 , 3 Estrogen receptor (ER) expression has been recognized as an important player in the initiation and progression of breast cancer. 4 Selective estrogen receptor degraders (SERDs) represent important options for endocrine treatment in breast cancer. LY3484356 (imlunestrant) is a next‐generation, oral SERD that acts as a pure ER antagonist. Imlunestrant provides continuous inhibition of ER signaling, with the aim of improving outcomes for patients with ER‐positive advanced breast cancer.
The recommended dosage of imlunestrant is 400 mg once daily, orally, on an empty stomach at least 2 h before food, or 1 h after food, 5 as imlunestrant exposure is affected by food intake. 6 , 7 Imlunestrant is eliminated in part by CYP3A4 oxidation and DDI studies with a strong CYP3A4 inhibitor (itraconazole) led to an approximately two‐fold increase (AUC0–∞, 111%; Cmax, 87%) in exposure while a significant decrease (AUC0–∞, 42%; Cmax, 29%) in exposure was observed following coadministration of a strong CYP3A4 inducer (carbamazepine) in healthy participants. 8 Treatment with a proton pump inhibitor (omeprazole) does not impact imlunestrant exposure and thus, PPIs may be taken concomitantly. 7 From an elimination perspective, a phase 1 mass balance study of the 400 mg dose identified that imlunestrant is mostly excreted in the feces (97.3%), with minimal urinary secretion (0.278%). 9 Metabolites and baseline PK at that dose level were characterized, and imlunestrant was shown to have an absolute bioavailability of ≈10%. 9
Hepatic impairment is a common condition, particularly among cancer patients, and it can alter the pharmacokinetics (PK) of anticancer drugs, which may adversely affect their safety. Given the role of CYP3A4 oxidation in the elimination of imlunestrant, and the intended patient population for imlunestrant may include individuals with hepatic impairment, it is essential to determine if dose adjustments of imlunestrant may be required to ensure safety, tolerability, and efficacy for these patients.
The study goal is to determine the effect of hepatic impairment on imlunestrant PK parameters and potential need for dose adjustments based on degree of hepatic impairment and the overall exposure‐safety/efficacy profile of imlunestrant. Herein we present the impact of hepatic impairment on the imlunestrant PK profile based on both Child‐Pugh (CP) and National Cancer Institute (NCI) classifications. The NCI classification can account for possible extrahepatic contributions to CP score often observed in cancer patients and is used in an exploratory capacity in this study. 10 , 11
Methods
The study was approved by appropriate independent ethics committees and institutional review boards and conducted according to the Declaration of Helsinki, the International Council for Harmonization Good Clinical Practice Guideline, and applicable regulatory requirements. The study is registered with ClinicalTrials.gov (NCT05440344). Written informed consent was obtained from all participants.
Study Design
This phase 1, open‐label, three‐site study was conducted between July 2022 and February 2024. Participants were assigned to four different groups based on their hepatic function: normal hepatic function, mild hepatic impairment (HI) (CP grade A [scores 5‐6]), moderate HI (CP grade B [scores 7–9]), and severe HI (CP grade C [scores 10–15]). At least six subjects were assigned to each arm, according to FDA guidance. 11 Participants were screened up to 28 days prior to enrollment, and eligible participants were admitted to a clinical research unit (CRU) on day −1, where they remained resident until day 5. Follow‐up visits were conducted from day 6 through day 11, or participants remained in the CRU until day 11.
On day 1, while fasting, participants received a single dose of imlunestrant. Those with normal hepatic function, mild HI, and moderate HI received 400 mg of imlunestrant, while participants with severe HI received 200 mg of imlunestrant.
Participants
Eligible female participants of non‐childbearing potential aged 18 years or older, with a body mass index (BMI) between 18 and 42 kg/m2, and in general good health, were included in the study. For participants with hepatic impairment, a diagnosis of chronic hepatic impairment was required for at least 6 months, with no significant clinical changes within the 90 days prior to study drug administration. Participants receiving or intending to receive strong inhibitors or inducers of CYP3A4 within 14 days prior to dosing until completion of the follow‐up visit, as well as participants who had previously received a SERD in the past 30 days prior to dosing, were excluded from the study. Ingestion of poppy seed, Seville orange, or grapefruit‐containing foods or beverages within 7 days prior to check‐in was not permitted. For participants with HI, use of concomitant medication known to interfere with hepatic metabolism within 2 weeks prior to dosing was not permitted. Participants with HI were matched with participants with normal hepatic function based on age (±10 years), sex, and BMI (±15%).
Objectives
The primary objective of this study was to evaluate the pharmacokinetic (PK) profile of imlunestrant following a single oral dose in fasting participants with varying levels of hepatic impairment, as determined by Child‐Pugh score, and compare them to participants with normal hepatic function. The secondary objective was to assess the safety and tolerability of imlunestrant in the study population.
Pharmacokinetics
Blood samples (<2 mL) for pharmacokinetic analysis were collected post single dose administration at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 192, 216, and 240 h after dosing (Figure 1). Imlunestrant concentrations were measured using validated high‐performance liquid chromatography with tandem mass spectrometry. 9 Long‐term storage was established up to 364 days at −20°C and 1393 days at −70°C. The intra‐day accuracy was −5.3% to 3.5%, and precision 1.2% to 4.5%. The inter‐day accuracy was −1.1% to 0.7%, and the precision 2.9% to 4.6%. The lower limit of quantification was 0.500 ng/mL, and the upper limit of quantification was 500 ng/mL. The fraction unbound in plasma was determined by equilibrium dialysis for 8 h at 37°C. Duplicate samples were assayed at 3, 4, and 8 h postdose following a single dose of imlunestrant. Pharmacokinetic parameters were calculated using standard noncompartmental methods.
Figure 1.
Study design. (a) Scheme for reclassification of patients from initial Child‐Pugh (CP) scores to National Cancer Institute (NCI) hepatic impairment criteria. Numbers of patients are indicated by circles, with level change indicated by an arrow; the NCI Severe Hepatic Impairment group was excluded from analysis due to sample size. (b) Sampling scheme for the study. aCP Grade A (scores 5–6); bCP Grade B (scores 7–9); cCP Grade C (scores 10–15); PK, pharmacokinetics.
An ANCOVA model was used to evaluate the log‐transformed PK parameters AUC(0‐tlast), AUC(0‐∞), and Cmax using the hepatic function group as a fixed effect and body weight as a covariate. The geometric least square means (GLSM) for each group, GLSM ratios between each hepatic impairment group versus the control group, and the corresponding 90% CIs were estimated from the ANCOVA model. Results were considered to be significant if the 90% CIs excluded unity.
The same analysis was repeated using the dose‐normalized PK parameters DN‐AUC(0‐tlast), DN‐AUC(0‐∞), and DN‐Cmax to assess the difference in participants with severe hepatic impairment (Group 4, test) compared to matched healthy participants with normal hepatic function (Group 1, reference function). Because imlunestrant exhibits reasonably dose‐proportional pharmacokinetics within the 200–400 mg range, dose normalization was employed to allow for meaningful comparisons between groups despite differences in administered doses to ensure that participants with severe hepatic impairment were not exposed to doses exceeding the highest approved recommended dosage. 5 , 12
The ANCOVA model was also used to evaluate differences in unbound PK parameters. Specifically, AUC(0‐tlast),u, AUC(0‐∞),u, and Cmax,u were compared between participants with hepatic impairment (test) and matched healthy participants with normal hepatic function (reference).
To evaluate PK parameters based on Child‐Pugh classification, PK parameters AUC(0‐∞), Cmax, and CL/F were plotted by Child‐Pugh classification parameters separately, including the control group with Child‐Pugh scores set to zero. A regression line and corresponding 90% CI from a simple linear model were plotted.
The effect of hepatic impairment on plasma protein binding of imlunestrant was evaluated using descriptive statistics of plasma protein binding data.
Aside from PK parameters analysis using the Child‐Pugh classification, an exploratory analysis using the National Cancer Institute (NCI) classification of hepatic impairment by total bilirubin (TB) and aspartate aminotransferase (AST) parameters relative to upper limit of normal (ULN) was performed. Patients were classified as having normal hepatic function (TB and AST ≤ ULN), mild HI (TB ≤1.5x ULN or AST > ULN), moderate HI (TB >1.5−3x ULN), and severe HI (TB >3x ULN). The analysis was conducted similarly to the primary analysis, with the group variable based on NCI classification. The same analysis was also conducted using the dose‐normalized PK parameters.
Safety
The safety population included all participants who received treatment. Safety data was summarized by severity, relationship to imlunestrant, and hepatic impairment group established by Child‐Pugh classification. AEs were coded according to the Medical Dictionary for Regulatory Activities (MeDRA v25.0). The data related to clinical laboratory analysis, vital signs, and electrocardiograms were included in the safety analysis.
Results
Participant Characteristics
A total of 27 participants were enrolled and completed the study. All participants were women of non‐childbearing potential, with nine participants enrolled in the normal hepatic function group, and six enrolled in each of the mild, moderate, and severe hepatic impairment groups based on Child‐Pugh classification. There were no major protocol deviations.
Participant demographic and baseline characteristics are described in Table 1. Overall, the median age was 60 years, and the median BMI was 32.31 kg/m2.
Table 1.
Participant Demographic Data and Baseline Characteristics
| Child‐Pugh classification | |||||
|---|---|---|---|---|---|
| Normal hepatic function n = 9 | Mild hepatic impairment n = 6 | Moderate hepatic impairment n = 6 | Severe hepatic impairment n = 6 |
Overall n = 27 |
|
| Age, years (median, range) | 60.0 (52‐67) | 68.0 (61‐70) | 60.0 (45‐71) | 57.0 (53‐61) | 60.0 (45‐71) |
| Sex, N (%) | |||||
| Male | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Female | 9 (100%) | 6 (100%) | 6 (100%) | 6 (100%) | 27 (100%) |
| Race, N (%) | |||||
| American Indian or Alaska Native | 0 | 0 | 1 (16.7%) | 0 | 1 (3.7%) |
| Black or African American | 1 (11.1%) | 0 | 0 | 0 | 1 (3.7%) |
| White | 8 (89.0%) | 6 (100%) | 5 (83.3%) | 6 (100%) | 25 (92.6%) |
| Ethnicity, N (%) | |||||
| Not Hispanic or Latino | 5 (55.6%) | 1 (16.7%) | 3 (50.0%) | 3 (50.0%) | 12 (44.4%) |
| Hispanic or Latino | 4 (44.4%) | 5 (83.3%) | 3 (50.0%) | 3 (50.0%) | 15 (55.6%) |
| BMI (kg/m2) (median, range) | 31.0 (21.8–38.6) | 32.2 (21.6–41.8) | 32.0 (23.0–39.3) | 35.0 (25.8–39.5) | 32.3 (21.6, 41.8) |
Pharmacokinetics Based on Child‐Pugh Classification
The concentration–time profiles following administration of a single dose of imlunestrant are shown on linear and log‐linear scales (Figure 2; Figure S1, Supporting Information). The imlunestrant concentrations were similar in the normal hepatic function and mild, moderate, and severe hepatic impairment cohorts (Table 2). Imlunestrant exposures observed in participants with normal hepatic function or mild HI were similar to those in previous studies. 12 The geometric mean ratios and 90% CIs comparing the imlunestrant primary PK parameters in the normal hepatic function group with the hepatic impairment cohorts (AUC(0‐tlast), AUC(0‐∞), and Cmax) are shown in Table 3 and Figure S2, Supporting Information. There was no significant difference in imlunestrant AUC(0‐tlast), AUC(0‐∞), and Cmax between participants with mild hepatic impairment and participants with normal hepatic function. Relative to participants with normal hepatic function, there was an increase in AUC(0‐tlast) of 120% and AUC(0‐∞) of 122%, and no significant differences in Cmax in participants with moderate hepatic impairment. Further, there were increases in imlunestrant DN‐AUC(0‐tlast) of 191% and DN‐AUC(0‐∞) of 206%, and with no significant difference in DN‐Cmax in the severe hepatic impairment group relative to the normal hepatic function group (Table 3).
Figure 2.
Arithmetic mean (+ upper one‐sided standard deviation) plasma concentration–time profile of total imlunestrant based on Child‐Pugh classification. Concentrations are dose‐normalized.
Table 2.
Summary of Pharmacokinetic Parameters of Total Imlunestrant Based on Child‐Pugh Classification
| Geometric mean (Geometric CV%) [n] | ||||
|---|---|---|---|---|
|
PK parameters |
Normal hepatic function b n = 9 | Mild hepatic impairment a , b n = 6 | Moderate hepatic impairment a , b n = 6 | Severe hepatic impairment [Link] , b n = 6 |
| AUC(0‐tlast) (ng h/mL) | 1970 (51%) | 2410 (27%) | 4320 (50%) | 2820 (47%) |
| DN‐AUC(0‐tlast) (ng h/mL/mg) | 4.92 (51%) | 6.03 (27%) | 10.8 (50%) | 14.1 (47%) |
| AUC(0‐∞) (ng h/mL) | 2010 (50%) | 2470 (28%) | 4460 (51%) | 3040 (46%) |
| DN‐AUC(0‐∞) (ng h/mL/mg) | 5.01 (50%) | 6.18 (28%) | 11.2 (51%) | 15.2 (46%) |
| %AUC(tlast–∞) (%) | 1.68 (65%) | 1.91 (73%) | 3.02 (34%) | 6.74 (49%) |
| Cmax (ng/mL) | 58.0 (56%) | 74.9 (47%) | 87.6 (51%) | 46.2 (49%) |
| DN‐Cmax (ng/mL/mg) | 0.15 (56%) | 0.19 (47%) | 0.22 (51%) | 0.23 (49%) |
| tmax d (h) | 4.00 (2.00–6.00) | 4.02 (1.00–6.00) | 2.48 (1.00–8.00) | 3.50 (1.00–8.00) |
| t1/2 e (h) | 34.7 (26.2–51.7) | 40.5 (24.7–58.5) | 46.5 (38.2–56.7) | 63.2 (47.2–74.1) |
| CL/F (L/h) | 199 (50%) | 162 (28%) | 89.6 (51%) | 65.8 (46%) |
| Vz/F (L) | 9990 (45%) | 9460 (39%) | 6010 (44%) | 6000 (58%) |
| Vss/F (L) | 9960 (46%) | 8760 (33%) | 6170 (48%) | 5870 (53%) |
%AUC(tlast–∞), percentage of AUC(0‐∞) extrapolated; AUC(0‐∞), area under the concentration versus time curve from time zero to infinity; AUC(0‐tlast), area under the concentration versus time curve from time zero to time t, where t is the last time point with a measurable concentration; CL/F, apparent total body clearance of drug calculated after extra‐vascular administration; Cmax, maximum observed drug concentration; CV, coefficient of variation; DN, dose‐normalized; n, number of participants; t1/2, half‐life associated with the terminal rate constant in non‐compartmental analysis; tmax, time of maximum observed drug concentration; Vss/F, apparent volume of distribution at steady state following extra‐vascular administration; Vz/F, apparent volume of distribution during the terminal phase after extra‐vascular administration.
Based on Child‐Pugh's classification.
Imlunestrant dose 400 mg.
Imlunestrant dose 200 mg.
Median (minimum‐maximum).
Geometric mean (minimum‐maximum).
Table 3.
Effect of Hepatic Impairment on the Pharmacokinetic Parameters and Dose‐Normalized Pharmacokinetic Parameters of Total Imlunestrant Based on Child‐Pugh Classification
|
PK parameter |
Hepatic function/impairment group |
n |
GLSM |
Ratio of GLSM (impairment:normal) (90% CI) | GLSM unbound | Ratio of GLSM (impairment:normal) (90% CI) unbound |
|---|---|---|---|---|---|---|
| AUC(0‐tlast) (ng h/mL) | Normal (Reference) a | 9 | 1970 | 123 | ||
| Mild (Test) a | 6 | 2410 | 1.23 (0.82, 1.83) | 140 | 1.14 (0.72, 1.80) | |
| Moderate (Test) a | 6 | 4320 | 2.20 (1.47, 3.29) | 221 | 1.80 (1.13, 2.85) | |
| DN‐AUC(0‐tlast) (ng h/mL/mg) | Normal (Reference) a | 9 | 4.89 | 0.31 | ||
| Severe (Test) b | 6 | 14.2 | 2.91 (1.80, 4.70) | 0.68 | 2.22 (1.33, 3.70) | |
| AUC(0‐∞) (ng h/mL) | Normal (Reference) a | 9 | 2010 |
126 |
||
| Mild (Test) a | 6 | 2470 | 1.23 (0.83, 1.84) | 143 | 1.14 (0.72, 1.80) | |
| Moderate (Test) a | 6 | 4460 | 2.22 (1.49, 3.32) | 229 | 1.82 (1.15, 2.88) | |
| DN‐AUC(0‐∞) (ng h/mL/mg) | Normal (Reference) a | 9 | 5.00 | 0.31 | ||
| Severe (Test) b | 6 | 15.3 | 3.06 (1.90, 4.91) | 0.73 | 2.33 (1.40, 3.88) | |
| Cmax (ng/mL) | Normal (Reference) a | 9 | 57.9 | 3.63 | ||
| Mild (Test) a | 6 | 74.8 | 1.29 (0.82, 2.02) | 4.33 | 1.19 (0.73, 1.94) | |
| Moderate (Test) a | 6 | 87.6 | 1.51 (0.97, 2.37) | 4.49 | 1.24 (0.76, 2.01) | |
| DN‐Cmax (ng/mL/mg) | Normal (Reference) a | 9 | 0.14 | 0.009 | ||
| Severe (Test) b | 6 | 0.23 | 1.62 (0.97, 2.70) | 0.011 | 1.24 (0.75, 2.04) |
AUC(0‐∞), area under the concentration versus time curve from time zero to infinity; AUC(0‐tlast), area under the concentration versus time curve from time zero to time t, where t is the last time point with a measurable concentration; Cmax, maximum observed drug concentration; DN, dose‐normalized; GLSM, geometric least squares mean; n, number of participants.
Imlunestrant dose 400 mg.
Imlunestrant dose 200 mg.
Considering the unbound fraction of imlunestrant, there were no significant differences when imlunestrant was administered to participants with mild hepatic impairment compared to those with normal hepatic function. The mean percent unbound averaged over three timepoints was 0.0658, 0.0603, 0.0524, and 0.0478 for normal hepatic function and mild, moderate, and severe hepatic impairment, respectively (data not shown). However, when administered to participants with moderate and severe hepatic impairment, the unbound AUC(0‐tlast) showed an 80% and 122% increase, and the unbound AUC(0‐∞) an 82% and 133% increase, respectively (Table 3). No significant differences in unbound Cmax were observed. The protein binding of imlunestrant ranged from 99.93% to 99.96% for all participants and all timepoints, indicating no difference in plasma protein binding across timepoints selected, and no difference due to any degree of hepatic impairment or concentration.
Imlunestrant PK Parameters Based on NCI Classification
Hepatic function in oncology patients is often assessed using the NCI classification system. In this study, pharmacokinetic (PK) analyses were conducted based on both the Child‐Pugh and NCI classifications. Reclassification of patients between systems is described in Figure 1.
Nine participants were classified as having normal hepatic function according to the Child‐Pugh score. Most of these participants were also categorized as having normal hepatic function in the NCI classification. However, one participant was found to have mild hepatic impairment according to the NCI criteria.
Six participants were initially identified as having mild hepatic impairment in both classifications, while two were reclassified with normal hepatic function according to the NCI criteria. Six participants were classified as having moderate hepatic impairment by Child‐Pugh score. Of these, two were reclassified as having normal hepatic function, while four individuals were reclassified with mild hepatic impairment.
From the six participants classified with severe hepatic impairment with CP score, five were reclassified as having moderate hepatic impairment by the NCI classification. Considering this, the severe hepatic impairment group was excluded from the exploratory analyses by NCI Classification.
The analysis demonstrated significant increases in AUC(0‐tlast) and AUC(0‐∞) of 56% and Cmax of 50% when imlunestrant was administered to participants with mild hepatic impairment compared to those with normal hepatic function by the NCI classification. Additionally, for participants with moderate hepatic impairment, there were significant increases in DN‐AUC(0‐tlast) of 202%, DN‐AUC(0‐∞) of 215%, and DN‐Cmax of 73% when compared to participants with normal hepatic function (Table 4, Figure S3, Supporting Information).
Table 4.
Effect of Hepatic Impairment on the Pharmacokinetic Parameters and Dose‐Normalized Pharmacokinetic Parameters of Total Imlunestrant Based on NCI Classification
|
PK parameter |
Hepatic function/impairment group |
n |
GLSM |
Ratio of GLSM (impairment:normal) (90% CI) | GLSM unbound | Ratio of GLSM (impairment:normal) (90% CI) unbound |
|---|---|---|---|---|---|---|
| AUC(0‐tlast) (ng h/mL) | Normal (Reference) a | 12 | 2170 |
124 |
||
| Mild (Test) a | 9 | 3380 | 1.56 (1.10, 2.22) | 201 | 1.62 (1.16, 2.27) | |
| Moderate (Test) b | 5 | 3270 | 1.51 (0.99, 2.31) | 166 | 1.34 (0.90, 2.02) | |
| DN‐AUC(0‐tlast) (ng h/mL/mg) | Normal (Reference) a | 12 | 5.42 | 0.31 | ||
| Mild (Test) a | 9 | 8.45 | 1.56 (1.10, 2.22) | 0.50 | 1.62 (1.16, 2.27) | |
| Moderate (Test) b | 5 | 16.3 | 3.02 (1.97, 4.62) | 0.83 | 2.69 (1.79, 4.03) | |
| AUC(0‐∞) (ng h/mL) | Normal (Reference) a | 12 | 2220 | 127 | ||
| Mild (Test) a | 9 | 3460 | 1.56 (1.10, 2.22) | 206 | 1.62 (1.15, 2.27) | |
| Moderate (Test) b | 5 | 3510 | 1.58 (1.03, 2.42) | 179 | 1.40 (0.93, 2.12) | |
| DN‐AUC(0‐∞) (ng h/mL/mg) | Normal (Reference) a | 12 | 5.56 | 0.32 | ||
| Mild (Test) a | 9 | 8.65 | 1.56 (1.09, 2.22) | 0.51 | 1.62 (1.15, 2.27) | |
| Moderate (Test) b | 5 | 17.5 | 3.15 (2.05, 4.85) | 0.89 | 2.81 (1.86, 4.24) | |
| Cmax (ng/mL) | Normal (Reference) a | 12 | 59.1 | 3.38 | ||
| Mild (Test) a | 9 | 88.7 | 1.50 (1.05, 2.14) | 5.28 | 1.56 (1.10, 2.21) | |
| Moderate (Test) b | 5 | 51.2 | 0.87 (0.56, 1.33) | 2.61 | 0.77 (0.51, 1.18) | |
| DN‐Cmax (ng/mL/mg) | Normal (Reference) a | 12 | 0.15 | 0.0085 | ||
| Mild (Test) a | 9 | 0.22 | 1.50 (1.05, 2.14) | 0.013 | 1.56 (1.10, 2.21) | |
| Moderate (Test) b | 5 | 0.26 | 1.73 (1.13, 2.67) | 0.013 | 1.54 (1.01, 2.36) |
AUC(0‐∞), area under the concentration versus time curve from time zero to infinity; AUC(0‐tlast), area under the concentration versus time curve from time zero to time t, where t is the last time point with a measurable concentration; Cmax, maximum observed drug concentration; DN, dose‐normalized; GLSM, geometric least squares mean; n, number of participants.
Imlunestrant dose 400 mg.
Imlunestrant dose 200 mg.
Safety
The administration of a single oral dose of 400 mg imlunestrant in the fasted state was well tolerated among healthy females of non‐childbearing potential with mild to moderate hepatic impairment based on Child‐Pugh and National Cancer Institute classifications. Similarly, the 200 mg dose was also well tolerated in individuals with severe hepatic impairment. There were no fatalities or discontinuations due to adverse events (AEs). There were no clinically significant findings in vital signs or laboratory tests. One serious adverse event (SAE), portal vein thrombosis, was reported by a participant with moderate hepatic impairment by CP and mild hepatic impairment by NCI classifications; however, this was not considered related to the administration of imlunestrant. There were no imlunestrant discontinuations due to adverse events.
Two participants with moderate hepatic impairment and two participants with severe hepatic impairment reported TEAEs. Most TEAEs were mild in severity, and the only TEAEs reported by more than one participant were nausea and headache (Table 5).
Table 5.
Summary of Adverse Events Based on Child‐Pugh Classification
|
Normal hepatic function n = 9 |
Mild hepatic function n = 6 |
Moderate hepatic impairment n = 6 |
Severe hepatic impairment n = 6 |
|||||
|---|---|---|---|---|---|---|---|---|
| TEAEs | TRAEs | TEAEs | TRAEs | TEAEs | TRAEs | TEAEs | TRAEs | |
| Patients with ≥1 AE | 0 | 0 | 0 | 0 | 2(33.3%) | 1(16.7%) | 2(33.3%) | 1(16.7%) |
| Adverse event (N%) | ||||||||
| Nausea | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 0 |
| Headache | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 |
| Upper abdominal pain | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Arthralgia | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Back pain | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Fall | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Insomnia | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Portal vein thrombosis | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Pruritus | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Rash | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Vomiting | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
TEAE, treatment‐emergent adverse event; TRAE, treatment‐related adverse event; n, number of participants; N, number of occurrences.
Discussion
The PK analysis of imlunestrant in participants with varying degrees of hepatic impairment revealed findings of potential clinical relevance. In participants with mild hepatic impairment by Child‐Pugh classification, there were no significant differences in the exposure profiles of imlunestrant compared to those with normal hepatic function. However, participants with moderate and severe hepatic impairment (CP) exhibited substantial increases in the area under the curve (AUC) for both total and unbound imlunestrant, indicating higher systemic exposure. Specifically, moderate hepatic impairment resulted in a 120% increase in AUC(0‐tlast) and a 122% increase in AUC(0‐∞), while severe hepatic impairment led to increases of 191% and 206%, respectively. These findings demonstrate that hepatic impairment significantly affects the metabolism and clearance of imlunestrant, necessitating consideration of dosing adjustments in this population.
Hepatic insufficiency can result in large increases in AUC for drugs that are cytochrome p450 (CYP) substrates with high clearance. 13 , 14 While ≈2‐fold increases in AUC were observed with imlunestrant treatment in patients with moderate and severe hepatic impairment, these changes are small compared to drugs that are highly metabolized by CYPs and are likely to be manageable with dose adjustment. These results are consistent with previous studies on other SERDs and anticancer drugs, which have shown altered pharmacokinetics in patients with hepatic dysfunction and the necessity of dose adjustments. 15 , 16 , 17 , 18 The consistency of these findings across different SERDs underscores the importance of evaluating hepatic function when prescribing these medications.
The results of this study have several practical and theoretical implications. Clinically, the significant increases in imlunestrant exposure in participants with moderate and severe hepatic impairment suggest that dose adjustments may be necessary to avoid potential toxicity. Based on the findings, a dose reduction to 200 mg once daily for patients with severe and moderate hepatic impairment is recommended. This dose reduction would bring imlunestrant exposure closer to that of the equivalent exposure of 400 mg tested in the EMBER‐3 phase 3 trial, which has been shown to be safe and efficacious. 19
This study has several limitations that should be acknowledged. The sample size was relatively small, with only six participants in each CP hepatic impairment group, which may limit the generalizability of the findings. Additionally, the study was conducted in a controlled clinical setting, which may not fully capture the variability in hepatic function seen in real‐world patients.
Based on the findings and limitations of this study, several potential directions for future research can be proposed. Continued surveillance and evaluation in oncology patients with hepatic impairment would improve understanding of the observed changes in imlunestrant exposure in this population. Additionally, research on the use of biomarkers to predict hepatic impairment and guide dosing adjustments could further enhance personalized medicine approaches for patients receiving imlunestrant.
The exploratory analysis using the National Cancer Institute (NCI) classification of hepatic impairment provided additional insights. The NCI criteria reclassified some participants differently compared to the Child‐Pugh classification, particularly the downgrading of moderate and severe impairment groups, as is commonly observed between these classification systems. 10 Consequently, a dose adjustment may be required at different hepatic impairment levels for each. Understanding which class criteria are being used could be important for effective patient dose adjustment. Despite these reclassifications, the overall trends in PK parameters were consistent between the two classification systems. This consistency reinforces the robustness of the findings and supports the use of either classification system in clinical practice, although the NCI classification may be more relevant for oncology patients.
Conclusions
In conclusion, this phase 1 study demonstrated significant alterations in the pharmacokinetics of imlunestrant in participants with moderate and severe hepatic impairment by Child‐Pugh classification and dose adjustments in this patient population from 400 to 200 mg are recommended. 5 The findings contribute to the growing body of evidence on the impact of hepatic dysfunction on the metabolism of various drugs and underscore the importance of personalized dosing strategies to ensure the safety, efficacy, and tolerability in patients with hepatic impairment. To this end, additional surveillance and real‐world evidence are likely to further inform recommendations in hepatically‐impaired cancer patients to evaluate the impacts of dose adjustment recommendations on long‐term safety and efficacy for imlunestrant.
Author Contributions
All authors conceived or designed the work. Elaine Shanks acquired data. Amita Datta‐Mannan, Eunice Yuen, Stephen David Hall, Vivian Rodriguez Cruz, and Xeujing Aimee Wang analyzed and interpreted data. Amita Datta‐Mannan, Elaine Shanks, Vivian Rodriguez Cruz, and Xuejing Aimee Wang drafted the manuscript and all authors contributed to critical review during the process.
Conflicts of Interest
Amita Datta‐Mannan, Stephanie White, Elaine Shanks, Eunice Yuen, Vivian Rodriguez Cruz, and Xuejing Aimee Wang are current employees, and Stephen David Hall is a former employee of Eli Lilly and Company. All may own stock/stock options in Eli Lilly and Company.
Funding
This study was funded by Eli Lilly and Company.
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Acknowledgments
We thank the participants, investigators, and staff of J2J‐MC‐JZLG. Joana Cruz Pereira and Benjamin Spears, of Eli Lilly and Company, provided medical writing support for this manuscript.
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