Inluriyo Drug Information

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

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 . 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

General Disorders and

Administration Site Conditions Fatigue b 23 0.3 14

Gastrointestinal Disorders Diarrhea 22 0.6 12 0.0 Nausea 17 0.3 13 0.0

Constipation 10 0 6

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

Neutrophils decreased 26 4 29 4.7 Platelets decreased 16 1.8 14 1.3

Chemistry Calcium decreased 26 0 19

Aspartate aminotransferase increased 25 1.9 27 2.3 Alanine aminotransferase increased 21 1.3

23

Effects of Other Drugs on

INLURIYO Strong CYP3A Inhibitors Avoid concomitant use of INLURIYO with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce the dosage of INLURIYO . Imlunestrant is a CYP3A substrate. Concomitant use of a strong CYP3A inhibitor increases imlunestrant exposure , which may increase the risk of INLURIYO-associated adverse reactions.

Strong CYP3A Inducers Avoid concomitant use of INLURIYO with strong CYP3A inducers. If concomitant use cannot be avoided, increase the dosage of INLURIYO. Imlunestrant is a CYP3A substrate. Concomitant use of a strong CYP3A inducer decreases imlunestrant exposure , which may reduce effectiveness of INLURIYO.

Effects of

INLURIYO on Other Drugs P-gp or BCRP Substrates Avoid concomitant use unless otherwise recommended in the Prescribing Information for P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions. Imlunestrant inhibits both P-gp and BCRP. Imlunestrant increases exposure of P-gp and BCRP substrates, which may increase the risk of adverse reactions related to these substrates.

Pregnancy Risk Summary Based on findings in animals and its mechanism of action, INLURIYO can cause fetal harm when administered to a pregnant woman . There are no available human data on INLURIYO use in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of imlunestrant to pregnant rats during the period of organogenesis led to embryo-fetal mortality and structural abnormalities at maternal exposures below the human exposure at the recommended dose based on AUC ( see Data ). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown.

However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data In an embryo-fetal development study, imlunestrant was administered orally to pregnant rats during the period of organogenesis from gestation day 6 to 17 at doses of 0.3, 3, and 30 mg/kg/day. Imlunestrant caused embryo-fetal mortality (increased resorption, reduced number of live fetuses) at ≥0.3 mg/kg/day, approximately 0.1 times the human AUC at the recommended dose.

Early delivery, fetal malformations (including small jaw, protruding tongue, malrotated, and hyperextended hindlimb) and fetal variations (edema localized subcutis) were observed at ≥3 mg/kg/day, approximately 1 time the human AUC at the recommended dose.

Pediatric Use The safety and effectiveness of INLURIYO have not been established in pediatric patients.