Inluriyo imlunestrant 200 mg Tablet, Film Coated, 28-count — NDC 0002-1717-28 (Billing 00002-1717-28)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Imlunestrant is an estrogen receptor (ER) antagonist that binds to ERα. In vitro, imlunestrant induced degradation of ERα, leading to inhibition of ER-dependent gene transcription and cellular proliferation in ER+ breast cancer cells. Imlunestrant demonstrated in vitro and in vivo anti-tumor activity in ER+ breast cancer xenograft models, including models with ESR1 mutations.

12.2Pharmacodynamics Imlunestrant exposure-response relationships and the time course of pharmacodynamics have not been fully characterized. Cardiac Electrophysiology At 2 times the mean maximum concentration observed with the approved recommended dose, a mean increase in the QTc interval >20 msec was not observed.

12.3Pharmacokinetics Imlunestrant pharmacokinetics were observed at steady state at the approved recommended dosage and are presented as mean (%CV) unless otherwise specified. The maximum concentration (C max ) of imlunestrant is 141 ng/mL (45%) and the area under the concentration-time curve (AUC) is 2,400 ng*h/mL (46%). Imlunestrant C max and AUC increase in a dose proportional manner over a dosage range of 200 mg to 1,200 mg (0.5 to 3 times the approved recommended dosage) once daily.

Steady-state is reached in approximately 6 days and the accumulation is 2.3-fold based on AUC. Absorption Imlunestrant absolute oral bioavailability after a single oral 400 mg dose is 10% (32%). Imlunestrant median (min, max) time to maximum plasma concentration (T max ) is 4 (2, 8) hours.

Effect of Food Imlunestrant AUC increased 2-fold and C max increased 3.6-fold following administration with a low-fat meal (approximately 475 calories with 13% fat, 16% protein, and 71% carbohydrates). The effect of high-fat meal (approximately 800-1,000 calories with 500-600 calories from fat) on imlunestrant exposures is unknown. Distribution The apparent (oral) volume of distribution is 8,120 L (69%).

Imlunestrant protein binding is >99% and is not concentration dependent. Elimination Imlunestrant elimination half-life is 30 hours with an estimated apparent clearance of 166 L/h (51%). Metabolism Imlunestrant is metabolized by sulfation, CYP3A4, and direct glucuronidation (UGT1A1, 1A3, 1A8, 1A9, 1A10).

Excretion After a single dose of radiolabeled imlunestrant 400 mg to healthy subjects, 97% of the dose was recovered in feces (62% unchanged) and 0.3% in urine. Specific Populations No clinically significant differences in the pharmacokinetics of imlunestrant based on age (28 to 95 years), race (64% White, 23% Asian, and 5% Black or African American), ethnicity (74% non-Hispanic/Latino, 17% Hispanic/Latino), body weight (36 to 145 kg), mild to moderate (eGFR 30 to 89 mL/min, estimated by CKD-EPI equation) renal impairment, or UGT1A1 genetic polymorphisms (e.g., UGT1A1*1/*28 or UGT1A1*28/*28).

The effect of severe (eGFR 15 to 29 mL/min) renal impairment and renal impairment requiring dialysis on imlunestrant pharmacokinetics is unknown. Patients with Hepatic Impairment Imlunestrant AUC increased 2.2-fold in subjects with moderate hepatic impairment (Child-Pugh B) and 3.1-fold in subjects with severe hepatic impairment (Child-Pugh C). No clinically significant differences in the pharmacokinetics of imlunestrant were observed in subjects with mild hepatic impairment (Child-Pugh A).

Drug Interaction Studies Clinical Studies Strong CYP3A Inhibitors : Imlunestrant AUC increased 2.1-fold and C max increased 1.9-fold following concomitant use of itraconazole (strong CYP3A inhibitor) for multiple days. Strong CYP3A Inducers : Imlunestrant AUC decreased by 42% and C max decreased by 29% following concomitant use of carbamazepine (strong CYP3A inducer) for multiple days. P-gp Substrates: Digoxin (P-gp substrate) AUC increased 1.4-fold and C max increased 1.6-fold following concomitant use of imlunestrant.

BCRP Substrates: Rosuvastatin (BCRP substrate) AUC increased 1.5-fold and C max increased 1.6-fold following concomitant use with im… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Imlunestrant is an estrogen receptor (ER) antagonist that binds to ERα. In vitro, imlunestrant induced degradation of ERα, leading to inhibition of ER-dependent gene transcription and cellular proliferation in ER+ breast cancer cells. Imlunestrant demonstrated in vitro and in vivo anti-tumor activity in ER+ breast cancer xenograft models, including models with ESR1 mutations.

12.3Pharmacokinetics Imlunestrant pharmacokinetics were observed at steady state at the approved recommended dosage and are presented as mean (%CV) unless otherwise specified. The maximum concentration (C max ) of imlunestrant is 141 ng/mL (45%) and the area under the concentration-time curve (AUC) is 2,400 ng*h/mL (46%). Imlunestrant C max and AUC increase in a dose proportional manner over a dosage range of 200 mg to 1,200 mg (0.5 to 3 times the approved recommended dosage) once daily.

Steady-state is reached in approximately 6 days and the accumulation is 2.3-fold based on AUC. Absorption Imlunestrant absolute oral bioavailability after a single oral 400 mg dose is 10% (32%). Imlunestrant median (min, max) time to maximum plasma concentration (T max ) is 4 (2, 8) hours.

Effect of Food Imlunestrant AUC increased 2-fold and C max increased 3.6-fold following administration with a low-fat meal (approximately 475 calories with 13% fat, 16% protein, and 71% carbohydrates). The effect of high-fat meal (approximately 800-1,000 calories with 500-600 calories from fat) on imlunestrant exposures is unknown. Distribution The apparent (oral) volume of distribution is 8,120 L (69%).

Imlunestrant protein binding is >99% and is not concentration dependent. Elimination Imlunestrant elimination half-life is 30 hours with an estimated apparent clearance of 166 L/h (51%). Metabolism Imlunestrant is metabolized by sulfation, CYP3A4, and direct glucuronidation (UGT1A1, 1A3, 1A8, 1A9, 1A10).

Excretion After a single dose of radiolabeled imlunestrant 400 mg to healthy subjects, 97% of the dose was recovered in feces (62% unchanged) and 0.3% in urine. Specific Populations No clinically significant differences in the pharmacokinetics of imlunestrant based on age (28 to 95 years), race (64% White, 23% Asian, and 5% Black or African American), ethnicity (74% non-Hispanic/Latino, 17% Hispanic/Latino), body weight (36 to 145 kg), mild to moderate (eGFR 30 to 89 mL/min, estimated by CKD-EPI equation) renal impairment, or UGT1A1 genetic polymorphisms (e.g., UGT1A1*1/*28 or UGT1A1*28/*28).

The effect of severe (eGFR 15 to 29 mL/min) renal impairment and renal impairment requiring dialysis on imlunestrant pharmacokinetics is unknown. Patients with Hepatic Impairment Imlunestrant AUC increased 2.2-fold in subjects with moderate hepatic impairment (Child-Pugh B) and 3.1-fold in subjects with severe hepatic impairment (Child-Pugh C). No clinically significant differences in the pharmacokinetics of imlunestrant were observed in subjects with mild hepatic impairment (Child-Pugh A).

Drug Interaction Studies Clinical Studies Strong CYP3A Inhibitors : Imlunestrant AUC increased 2.1-fold and C max increased 1.9-fold following concomitant use of itraconazole (strong CYP3A inhibitor) for multiple days. Strong CYP3A Inducers : Imlunestrant AUC decreased by 42% and C max decreased by 29% following concomitant use of carbamazepine (strong CYP3A inducer) for multiple days. P-gp Substrates: Digoxin (P-gp substrate) AUC increased 1.4-fold and C max increased 1.6-fold following concomitant use of imlunestrant.

BCRP Substrates: Rosuvastatin (BCRP substrate) AUC increased 1.5-fold and C max increased 1.6-fold following concomitant use with imlunestrant. Other Drugs: No clinically significant differences in the pharmacokinetics of imlunestrant were observed when used concomitantly with omeprazole (gastric acid-reducing agent) or quinidine (P-gp inhibitor). No clinically significant differences in the pharmacokinetics of midazolam (CYP3A substrate), repaglinide (CYP2C8 substrate), omeprazole (CYP2C19 substrate), or dextromethorphan (CYP2D6 substrate) were observed when used concomitantly with imlunestrant.

In Vitro Studies CYP Enzymes: Imlunestrant is an inhibitor of CYP2B6 and CYP2C9 but is not an inhibitor of CYP1A2. Imlunestrant is not an inducer of CYP1A2, CYP2B6, or CYP2C9. Transporter Systems: Imlunestrant is not a substrate of BCRP, OCT1, OATP1B1, or OATP1B3.

12.2Pharmacodynamics Imlunestrant exposure-response relationships and the time course of pharmacodynamics have not been fully characterized. Cardiac Electrophysiology At 2 times the mean maximum concentration observed with the approved recommended dose, a mean increase in the QTc interval >20 msec was not observed.

14 CLINICAL STUDIES The efficacy of INLURIYO was evaluated in EMBER-3 (NCT04975308), a randomized, open-label, active-controlled, multicenter trial that enrolled 874 adult patients with ER+, HER2- locally advanced or metastatic breast cancer, who were previously treated with an aromatase inhibitor either alone or in combination with a CDK4/6 inhibitor. Patients were excluded if they were eligible to receive a PARP inhibitor. Patients were required to have progressed: Within 12 months of completing neoadjuvant or adjuvant aromatase inhibitor therapy with no systemic treatment for recurrent disease or Greater than 12 months after neoadjuvant or adjuvant endocrine therapy or de novo metastatic disease and had progressed on only one line of aromatase inhibitor therapy.

Patients were randomized 1:1:1 to INLURIYO 400 mg orally once daily; or investigator's choice of endocrine therapy [fulvestrant 500 mg IM on days 1, 15, 29, and once monthly thereafter (n=111) or exemestane 25 mg orally once daily (n=6)]; or an additional investigational combination regimen. 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). ESR1 m status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) analysis using the Guardant360 CDx assay and was limited to specific ESR1 mutations in the ligand binding domain.

Patients were treated until disease progression or unacceptable toxicity. The major efficacy outcome was investigator assessed progression-free survival (PFS) according to RECIST v1.1. Other efficacy measures included overall survival (OS), blinded independent review committee (BIRC)-assessed PFS, and objective response rate (ORR).

Among the patients on the INLURIYO arm or investigator's choice of endocrine therapy who were positive for ESR1 m (N=256), the median age was 61 years (range: 28-85 years); all patients were female, of which 11% were pre/perimenopausal; 61% were White, 26% Asian, 4% Black, 4% were American Indian or Alaskan Native, 4.7% missing, 0.8% multiple, 19% were Hispanic/Latino; and baseline ECOG performance status was 0 (63%) or 1 (37%). Most patients had visceral metastasis (59%) at baseline. Of the patients enrolled, 21% had received no endocrine therapy and 79% had received one line of endocrine therapy in the advanced or metastatic setting.

Overall, 70% of patients were treated with a prior CDK4/6i, 2.3% treated in the adjuvant setting and 67% treated in the advanced or metastatic setting. The efficacy results from these patients are summarized in Table 5 and Figure 1 . There was a statistically significant difference in investigator-assessed PFS in the ESR1 m population for INLURIYO compared to investigator's choice of endocrine therapy (fulvestrant or exemestane).

PFS assessment based on a BIRC was consistent with the investigator assessment. At the time of PFS analysis, overall survival data was immature with 31% of deaths in the ESR1 m population. Table 5: Efficacy Results for Patients with ESR1m in EMBER-3 a Investigator Assessed b per RECIST v1.1 c Based on the stratified Cox proportional hazard model d Two-sided p-value based on stratified log-rank test (compared to a significance level of 0.04) INLURIYO N=138 Fulvestrant or Exemestane N=118 Progression-free Survival (PFS) a, b Number of PFS Events, n (%) 109 (79) 102 (86) Median in months (95% CI) 5.5 (3.9, 7.4) 3.8 (3.7, 5.5) Hazard Ratio (95% CI) c 0.62 (0.46, 0.82) p-value d 0.0008 Objective Response Rate b Patients with Measurable Disease 112 91 ORR (95% CI) 14.3 (7.8, 20.8) 7.7 (2.2, 13.2) Complete response rate, % 0.9 0 Partial response rate, % 13.4

7.7Figure 1: Kaplan-Meier Plot of Investigator-Assessed PFS for Patients with ESR1 m, Treated with INLURIYO or Fulvestrant/Exemestane in EMBER-3 Figure 1

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies have not been conducted with imlunestrant. Mutagenesis Imlunestrant was not mutagenic in the bacterial reverse mutation (Ames) assay. Imlunestrant was clastogenic in an in vitro human lymphocyte micronucleus assay.

Imlunestrant was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA breaks in the liver and duodenum comet assays. Impairment of Fertility Fertility studies with imlunestrant in animals have not been conducted. In repeat-dose toxicity studies up to 6 months in rats and 3 months in cynomolgus monkeys, oral administration of imlunestrant resulted in follicular cysts in the ovary and atrophy in the vagina, cervix, and uterus at doses ≥ 10 mg/kg/day in rats (≥ 4 times the human AUC at the recommended dose) and ≥ 15 mg/kg/day in cynomolgus monkeys (≥1 times the human AUC at the recommended dose).

Decreased sperm and cellular debris in the epididymis and spermatid retention in the testis were observed in male rats at ≥10 mg/kg/day. The effects of imlunestrant on male and female reproductive organs were reversible in rats following a 3-month recovery period. Reversibility was not assessed in cynomolgus monkeys.

13.2Animal Toxicology and/or Pharmacology In a 6-month repeat-dose toxicity study, oral administration of imlunestrant to rats resulted in epithelial hyperplasia in the urinary bladder, granulosa cell hyperplasia in the ovary, and hyperplasia in the mammary gland at doses ≥ 10 mg/kg/day (≥ 4 times the human AUC at the recommended dose). These effects, except urinary bladder effects, were reversible after a 3-month recovery period.