Vepdegestrant

1 INDICATIONS AND USAGE VEPPANU 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, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. VEPPANU is a heterobifunctional protein degrader 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, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vepdegestrant is a heterobifunctional protein degrader that binds to estrogen receptor (ER) and the E3 ligase cereblon (CRBN). This interaction results in the degradation cascade through CRBN-mediated polyubiquitination and degradation of ER by the proteasome, leading to reduction of ER protein levels in breast cancer cells. Vepdegestrant induced degradation of wild-type (WT) and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro and demonstrated antitumor activity in vivo in both WT and mutant ESR1 breast cancer models. 12.2 Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response of vepdegestrant have not been fully characterized. Cardiac Electrophysiology The largest mean increase in QTc interval was 12 ms (upper confidence interval = 15 ms) after administration of vepdegestrant at the recommended dosage of 200 mg once daily in patients with ESR1 mutation-positive breast cancer. 12.3 Pharmacokinetics Vepdegestrant pharmacokinetics were observed at steady state in patients with ER+/HER2- breast cancer at the approved recommended dosage of 200 mg once daily and are presented as mean (coefficient of variation (CV%)) unless otherwise specified. Vepdegestrant maximum concentration (C max ) is 926 ng/mL (39%), and the total systemic exposure (AUC) is 17,155 ng•hr/mL (36%). Vepdegestrant AUC and C max increase in an approximately dose proportional manner over the dose range of 100 mg (0.5 times the approved recommended dose) to 500 mg (2.5 times the approved recommended dose). Vepdegestrant accumulation is approximately 1.4-fold for AUC and 1.3-fold for C max . Vepdegestrant steady state is reached in approximately 7 days. Absorption Vepdegestrant median (min, max) time to maximum plasma concentration (T max ) is approximately 6 (4, 8) hours. Effect of Food Vepdegestrant AUC increased 2.9-fold and C max 3.2-fold following administration with a high-fat meal (approximately 800 to 1,000 calories; ≥50% fat). Distribution Vepdegestrant plasma protein binding is >99%. The apparent (oral) volume of distribution is 764 L (26%) following a single 200 mg dose. Elimination Vepdegestrant effective elimination half-life is 19 hours (50%) with an apparent (oral) clearance of 12 L/h (36%). Metabolism Vepdegestrant is primarily metabolized through direct sulfation via multiple SULT isoforms and oxidation via CYP3A4 and to a lesser extent by CYP2C8, CYP2C9 and CYP3A5. Unchanged total vepdegestrant represented 92% of total radioactivity in plasma. Excretion Following a single oral dose of radiolabeled vepdegestrant 200 mg to healthy subjects, approximately 68% of the dose was recovered in feces (18% unchanged) and 1.5% in urine (<0.02% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of vepdegestrant were observed based on age (26 to 89 years), sex, body weight (37 to 181 kg), race (60% White, 27% Asian,

2 DOSAGE AND ADMINISTRATION Select patients for treatment with VEPPANU based on the presence of ESR1 mutation. ( 2.1 ) Recommended Dosage: 200 mg orally once daily with food. ( 2.2 ) Interruption, dose reduction, or permanent discontinuation may be required due to adverse reactions. ( 2.3 ) 2.1 Patient Selection Select patients for treatment of ER-positive, HER2-negative advanced or metastatic breast cancer with VEPPANU based on the presence of ESR1 mutation(s) in plasma specimen using an FDA-authorized test [see Indications and Usage ( 1 ) and Clinical Studies ( 14 )] . Information on FDA-authorized tests for detection of ESR1 mutations in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage and Administration The recommended dosage of VEPPANU is 200 mg taken orally once daily with food [see Clinical Pharmacology ( 12.3 )] until disease progression or unacceptable toxicity. Swallow VEPPANU tablet(s) whole. Do not chew, crush, dissolve, or split prior to swallowing. Do not take VEPPANU tablets that are broken, cracked, or look damaged. If a patient misses a dose or vomits after taking a dose, the patient should take the next dose at the regularly scheduled time. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reduction for adverse reactions is 100 mg orally once daily. Permanently discontinue VEPPANU in patients who are unable to tolerate 100 mg orally once daily. The recommended dosage modifications for VEPPANU for adverse reactions are provided in Table 1 and Table 2 . Table 1: Dosage Modifications for Adverse Reactions (Except QTc Prolongation) CTCAE Severity Grade Dosage Modification Abbreviations: CTCAE=National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Grade 1 No dose modification is required. Grade 2 Consider interruption of VEPPANU until recovery to Grade ≤1 or baseline. Then resume VEPPANU at the same dose. Grade 3 First occurrence: Interrupt VEPPANU until recovery to Grade ≤1 or baseline. Then resume VEPPANU at the same dose or at the reduced dose at the discretion of the physician. If the Grade 3 toxicity recurs, interrupt VEPPANU until recovery to Grade ≤1 or baseline. Then resume VEPPANU at the reduced dose or discontinue VEPPANU at the discretion of the physician. Grade 4 First occurrence: Interrupt VEPPANU until recovery to Grade ≤1 or baseline. Then resume VEPPANU at the reduced dose. If a Grade 4 or intolerable adverse reaction recurs, permanently discontinue VEPPANU. Table 2: Dosage Modification and Management for QTc Prolongation QTc Prolongation Heart-rate corrected QTc using Fridericia's method. [see Warnings and Precautions ( 5.1 )] Dosage Modification and Management QTc >480 ms or >60 ms increase from baseline (and QTc ≤500 ms) Withhold until QTc resolves to ≤480 ms and ≤60 ms above baseline, then resume VEPPANU at the same dose. Identify and treat reversible causes (e.g., hypokalemia and hypomagnesemia). Initiate more frequent ECG monitoring. QTc >500 ms Withhold until QTc resolves to ≤480 ms and ≤60 ms above baseline, then: resume VEPPANU at the same dose if reversible cause is identified and corrected (e.g., hypokalemia and hypomagnesemia). resume VEPPANU at the reduced dose if no reversible cause is identified. Initiate more frequent ECG monitoring. Permanently discontinue if QTc >500 ms recurs. Torsade de Pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia Permanently discontinue VEPPANU. 2.4 Dosage Modifications for Drug Interactions Strong CYP3A Inhibitors Avoid concomitant use with strong CYP3A inhibitors in patients receiving VEPPANU 200 mg once daily. If concomitant use cannot be avoided, reduce VEPPANU from 200 mg once daily to 100 mg once daily [see Drug Interactions ( 7.1 )] . After a CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume VEPPANU 200 mg once daily. Avoid concomitant use with strong CYP3A inhibitors in patients receiving VEPPANU

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: QTc Interval Prolongation [see Warnings and Precautions ( 5.1 )] Most common ( > 10%) adverse reactions with VEPPANU, including laboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 VEPPANU was evaluated in patients with ER-positive, HER2-negative, advanced or metastatic breast cancer following endocrine therapy in VERITAC-2 [see Clinical Studies ( 14 )] . Patients received VEPPANU 200 mg orally once daily (N=312) or fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each subsequent 28-day cycle (N=307). Among patients who received VEPPANU, 33% were exposed for 6 months or longer and 6% were exposed for greater than one year. Serious adverse reactions occurred in 9% of patients who received VEPPANU. The serious adverse reactions included any fracture (1.3%), fall, hypercalcemia, hepatic injury, pneumonia, musculoskeletal pain (0.6% each), and QTc prolonged (0.3%). Fatal adverse reactions occurred in 1.0% of patients who received VEPPANU, including dyspnea, cerebral ischemia, and unknown cause (one patient each). Permanent discontinuation of VEPPANU due to an adverse reaction occurred in 2.9% of patients. Adverse reactions that resulted in permanent discontinuation of VEPPANU included increased alanine aminotransferase (ALT) and dyspnea (0.6% each). Dosage interruptions of VEPPANU due to an adverse reaction occurred in 14% of patients. Adverse reactions which required dosage interruption in >1% of patients included neutropenia (1.9%), anemia, hepatic injury, nausea, fatigue, and musculoskeletal pain (1.3% each). Dosage reductions of VEPPANU due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage reductions of VEPPANU included electrocardiogram QT prolonged, fatigue and musculoskeletal pain (0.3% each). The most common (≥10%) adverse reactions, including laboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation. Table 3 and Table 4 summarize adverse reactions and laboratory abnormalities in VERITAC-2, respectively. Table 3: Adverse Reactions (≥10%) in Patients with ER+, HER2-, Advanced or Metastatic Breast Cancer Who Received VEPPANU in VERITAC-2 Adverse reactions were graded using NCI CTCAE version 5.0. Adverse Reaction VEPPANU N=312 Fulvestrant N=307 All Grades % Grade 3 No Grade 4 events were reported. % All Grades % Grade 3 % Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Includes multiple related terms. 30 2.6 23 1 General Disorders and Administration Site Conditions Fatigue 29 1 16 1.3 Gastrointestinal Disorders Nausea 14 0 9 1 Constipation 10 0 3.3 0 Metabolism and Nutrition Disorders Decreased appetite 11 0.3 5 0 Investigations Electrocardiogram QT prolonged 10 1.6 1.3 0.3 Clinically relevant adverse reactions in <10% of patients who received VEPPANU included headache, hot flush, diarrhea, vomiting

5 WARNINGS AND PRECAUTIONS QTc Interval Prolongation : Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment with VEPPANU. Correct hypokalemia and hypomagnesemia prior to and during treatment. Repeat ECGs as clinically indicated. Withhold, reduce dose, or permanently discontinue VEPPANU based on severity. ( 5.1 ) Embryo-Fetal Toxicity : VEPPANU can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.2 , 8.1 , 8.3 ) 5.1 QTc Interval Prolongation VEPPANU can cause QT (QTc) interval prolongation [see Clinical Pharmacology ( 12.2 )] . In VERITAC-2, QTc interval prolongation was reported in 10% of patients; Grade 3 occurred in 1.6% of patients. The heart-rate corrected QTc interval using Fridericia's method was greater than 500 msec in 1.6% of patients, and the increase from baseline QTc was greater than 60 msec in 2.6% of patients. VEPPANU dose reduction was required for 0.3% of patients due to QTc interval prolongation [see Adverse Reactions ( 6.1 )] . Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to and during treatment with VEPPANU. Perform an ECG prior to initiation of treatment with VEPPANU, and do not initiate VEPPANU in patients with QTc > 470 msec. Repeat ECG approximately 4 weeks after initiating treatment and as clinically indicated. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, additional ECG monitoring may be necessary. Avoid concomitant use of VEPPANU with strong CYP3A inhibitors or drugs known to prolong the QTc interval. Reduce VEPPANU dose when concomitant use with strong CYP3A inhibitors cannot be avoided [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.1 , 7.3 ), and Clinical Pharmacology ( 12.2 )] . If concomitant use with other QTc-prolonging agents cannot be avoided, increase the frequency of ECG monitoring. Withhold, reduce dose, or permanently discontinue based on severity [see Dosage and Administration ( 2.3 )] . 5.2 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, VEPPANU can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of vepdegestrant to pregnant rats during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at maternal exposures below the recommended dose based on area under the curve (AUC). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] .

4 CONTRAINDICATIONS None. None. ( 4 )