Imlunestrant

1 INDICATIONS AND USAGE INLURIYO is indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 ( ESR1 )-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. INLURIYO TM is an estrogen receptor antagonist indicated for: treatment of adults with ER-positive, HER2-negative, ESR1 -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy ( 1 )

2 DOSAGE AND ADMINISTRATION Select patients for treatment based on the presence of ESR1 mutations. ( 2.1 ) The recommended dosage is 400 mg orally once daily, on an empty stomach. ( 2.2 ) Reduce the dose in patients with moderate or severe hepatic impairment ( 2.4 , 8.6 ) Dosage modifications may be required. ( 2.3 , 2.4 , 2.5 ) 2.1 Patient Selection Select patients for treatment of ER-positive, HER2-negative advanced or metastatic breast cancer with INLURIYO based on the presence of ESR1 mutation(s) in a plasma specimen using an FDA-approved test [see Indications and Usage ( 1 ) and Clinical Studies (14.1)] . Information on FDA-approved tests for the detection of ESR1 mutations in breast cancer is available at: https://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage and Administration The recommended dosage of INLURIYO is 400 mg orally once daily until disease progression or unacceptable toxicity. Take on an empty stomach at least 2 hours before food, or 1 hour after food [see Clinical Pharmacology ( 12.3 )] . Take INLURIYO tablets at approximately the same time daily. Swallow the tablets whole. Do not split, crush, or chew the tablets. Pre/perimenopausal women and men should receive a gonadotropin-releasing hormone agonist (GnRH) according to current clinical practice standards. If patient misses a dose by 6 or more hours or vomits, instruct the patient to take the next dose the following day at its scheduled time. 2.3 Dosage Modifications for Adverse Reactions The recommended INLURIYO dosage modifications for adverse reactions are provided in Tables 1 and 2 . The recommended dose reduction is to 200 mg once daily. Permanently discontinue INLURIYO in patients who are unable to tolerate 200 mg once daily. Table 1: INLURIYO Dosage Modification - Adverse Reactions (except hepatotoxicity) Grade INLURIYO Dosage Modifications Persistent or recurrent Grade 2 that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1 Suspend until toxicity resolves to baseline or ≤Grade 1. Resume INLURIYO at the same dose level. Grade 3 or 4 (except non-hepatic asymptomatic laboratory changes) Suspend until toxicity resolves to baseline or ≤Grade 1. Resume INLURIYO at next lower dose level. Table 2: INLURIYO Dosage Modification - Hepatotoxicity Abbreviation: ALT = alanine aminotransferase, AST = aspartate aminotransferase, TBL=total bilirubin, ULN = upper limit of normal. Monitor alanine aminotransferase (ALT)/aspartate aminotransferase (AST) during imlunestrant therapy as clinically indicated. Liver Transaminase INLURIYO Dosage Modifications Persistent or Recurrent: AST/ALT >3.0-5.0×ULN Suspend until toxicity resolves to baseline or to >ULN-3.0×ULN. Resume INLURIYO at the same dose level. If AST/ALT at baseline is within the normal range: AST/ALT >5.0-20×ULN Or If AST/ALT at baseline is above ULN: AST/ALT ≥3 × baseline (if AST/ALT≥1.5 x ULN at baseline) Or AST/ALT >8 × ULN (whichever is the lower threshold) Suspend until toxicity resolves to baseline or to >ULN-3.0×ULN. Resume INLURIYO at next lower dose level or discontinue if receiving 200 mg daily. AST/ALT >20.0×ULN Or ALT or AST ≥ 3 × ULN concurrent with TBL ≥ 2 × ULN (if ALT or AST < 1.5 × ULN at baseline), in the absence of cholestasis Or ALT or AST ≥ 2 × baseline concurrent with TBL ≥ 2 × ULN (if ALT or AST ≥ 1.5 × ULN at baseline), in the absence of cholestasis Discontinue INLURIYO. 2.4 Dosage in Patients with Hepatic Impairment The recommended dosage of INLURIYO for patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment is 200 mg once daily. Monitor for increased adverse reactions [see Clinical Pharmacology ( 12.3 )] . 2.5 Dosage Modifications for Drug Interactions Strong CYP3A Inhibitors Avoid concomitant use with strong CYP3A inhibitors. If concomitant use cannot be avoided, decrease the INLURIYO dosage to 200 mg once daily [see Drug Interactions ( 7.1 )] . Strong CYP3A Inducers Avoid concomitant use with strong CYP3A inducers. If concomitant use cannot be avoided, increase the INLURIYO dosage to 600 mg once daily [see Drug Interactions ( 7.1 )] .

6 ADVERSE REACTIONS The most common (incidence ≥10%) adverse reactions, including laboratory abnormalities were: hemoglobin decreased, musculoskeletal pain, calcium decreased, neutrophils decreased, AST increased, fatigue, diarrhea, ALT increased, triglycerides increased, nausea, platelets decreased, constipation, cholesterol increased, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of INLURIYO was evaluated in 651 patients with ER+, HER2- locally advanced or metastatic breast cancer previously treated with endocrine therapy with or without a prior CDK4/6 inhibitor in EMBER-3 [see Clinical Studies (14.1)] . Patients received INLURIYO 400 mg orally, once daily (n=327), or standard of care (n=324) consisting of either fulvestrant (n=292) or exemestane (n=32). Among patients who were treated with INLURIYO, the median duration of exposure was 5.6 months (range: 0.2 to 28.6 months) in EMBER-3. Serious adverse reactions occurred in 10% of patients who received INLURIYO. Serious adverse reactions in > 1% of patients included pleural effusion (1.2%). Fatal adverse reactions occurred in 1.8% of patients who received INLURIYO, including cardiac arrest, acute myocardial infarction, right ventricular failure, hypovolemic shock, and upper gastrointestinal hemorrhage (each 0.3%). Permanent treatment discontinuation of INLURIYO due to an adverse reaction occurred in 4.6% of patients. Adverse reactions which resulted in permanent discontinuation of INLURIYO included increased alanine aminotransferase (0.9%), abdominal pain, fatigue, fractured sacrum, hepatotoxicity, neuropathy peripheral, and pyrexia (each 0.3%). Dosage interruption of INLURIYO due to an adverse reaction occurred in 10% of patients. Adverse reactions which required dosage interruption in >0.5% were vomiting (1.5%); increased aspartate aminotransferase and COVID-19 (each 0.9%); and increased alanine aminotransferase, anemia, diarrhea, decreased neutrophil count, and pyrexia (each 0.6%). Dose reductions of INLURIYO due to an adverse reaction occurred in 2.4% of patients. Adverse reactions which required dose reductions were increased aspartate aminotransferase (0.6%); and increased alanine aminotransferase, anemia, fatigue, interstitial lung disease, nausea, neutropenia, and vomiting (each 0.3%). The most common (≥10%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, musculoskeletal pain, calcium decreased, neutrophils decreased, AST increased, fatigue, diarrhea, ALT increased, triglycerides increased, nausea, platelets decreased, constipation, cholesterol increased, and abdominal pain. Table 3 summarizes the adverse reactions in EMBER-3. Table 3: Adverse Reactions (≥10%) in Patients Who Received INLURIYO in EMBER-3 a Adverse reactions were graded using NCI CTCAE version 5.0. b Includes other related terms Adverse Reaction a INLURIYO N=327 Fulvestrant or Exemestane N=324 All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Musculoskeletal Disorders Musculoskeletal Pain 30 3.7 29 1.9 General Disorders and Administration Site Conditions Fatigue b 23 0.3 14 0.6 Gastrointestinal Disorders Diarrhea 22 0.6 12 0.0 Nausea 17 0.3 13 0.0 Constipation 10 0 6 0.3 Abdominal pain b 10 0.3 6 0.6 Clinically relevant adverse reactions (<10%) in patients who received INLURIYO included: vomiting (9%), headache (9%), cough (9%), decreased appetite (8%), hot flush (7%), pruritus (3.7%), dyspepsia (2.8%), and stomatitis (2.4%). Table 4 summarizes the laboratory abnormalities in EMBER-3. Table 4: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received INLURIYO in EMBER-3 a Graded according to NCI CTCAE version 5 b The denominator used to calculate the rate varied from 252 to 325 based on the number of patients with a baseline value and at least one post-treatment value. Lab Abnormality a INLURIYO b Fulvestrant or Exemestane b All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Hematology Hemoglobin decreased 30 1.2 35 3.4 Neutrophils decreased 26 4 29 4.7 Platelets decreased 16 1.8 14 1.3 Chemistry Calcium decreased 26 0 19 0.6 Aspartate aminotransferase increased 25 1.9 27 2.3 Alanine aminotransferase increased 21 1.3 23 1.0 Triglycerides increased 21 0 22 1.2 Cholesterol increased 10 0 12 0

12.3 Pharmacokinetics 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.