AHFS Class:

• Antineoplastic Agents 10:00

Brands:

• Veppanu^®

Generic Name(s):

• Vepdegestrant

Vepdegestrant, a heterobifunctional protein degrader, is an antineoplastic agent.1

Drug has the following uses:

Vepdegestrant 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.1

General

Vepdegestrant is available in the following dosage form(s) and strength(s):

Tablets: 100 mg and 200 mg1

Dosage

Adults

Dosage and Administration

• Select patients for treatment with vepdegestrant based on the presence of ESR1 mutation(s) in plasma specimen using an FDA-authorized test.1
• Recommended adult dosage is 200 mg orally once daily with food until disease progression or unacceptable toxicity.1
• Interruption, dose reduction, or permanent discontinuation may be required due to adverse reactions.1
• See Full Prescribing Information for dosage modifcation recommendations for adverse effects and drug interactions.1

Contraindications

None.1

Warnings/Precautions

QTc Interval Prolongation

Vepdegestrant can cause QT (QTc) interval prolongation.1 In the VERITAC-2 study, QTc interval prolongation was reported in 10% of patients; Grade 3 occurred in 1.6% of patients.1 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.1 Vepdegestrant dose reduction was required for 0.3% of patients due to QTc interval prolongation.1

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to and during treatment with vepdegestrant.1 Perform an ECG prior to initiation of treatment with vepdegestrant, and do not initiate vepdegestrant in patients with QTc >470 msec.1 Repeat ECG approximately 4 weeks after initiating treatment and as clinically indicated.1 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.1 Avoid concomitant use of vepdegestrant with strong CYP3A inhibitors or drugs known to prolong the QTc interval.1 Reduce vepdegestrant dose when concomitant use with strong CYP3A inhibitors cannot be avoided.1 If concomitant use with other QTc-prolonging agents cannot be avoided, increase the frequency of ECG monitoring.1 Withhold, reduce dose, or permanently discontinue based on severity.1

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, vepdegestrant can cause fetal harm when administered to a pregnant woman.1 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 AUC.1

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1 Advise females of reproductive potential to use effective contraception during treatment with vepdegestrant and for 2 weeks after the last dose.1 Advise male patients with female partners of reproductive potential to use effective contraception during treatment with vepdegestrant and for 2 weeks after the last dose.1

Specific Populations

Pregnancy

Based on findings in animals and its mechanism of action, vepdegestrant can cause fetal harm when administered to a pregnant woman.1 There are no available human data on the use of vepdegestrant in pregnant women to inform the drug-associated risk.1 In an animal reproduction study, oral administration of vepdegestrant to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal exposures below the recommended dose based on AUC.1 Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Lactation

There are no data on the presence of vepdegestrant or its metabolites in human milk, or its effects on milk production or the breastfed child.1 Because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with vepdegestrant and for 2 weeks after the last dose.1

Females and Males of Reproductive Potential

Vepdegestrant can cause fetal harm when administered to a pregnant woman.1 Verify the pregnancy status in females of reproductive potential prior to initiating vepdegestrant treatment.1 Advise females of reproductive potential to use effective contraception during treatment with vepdegestrant and for 2 weeks after the last dose.1 Advise male patients with female partners of reproductive potential to use effective contraception during treatment with vepdegestrant and for 2 weeks after the last dose.1

Based on findings from animal studies, vepdegestrant may impair fertility in females and males of reproductive potential.1 The effects of vepdegestrant on fertility were reversible in female animals.1

Pediatric Use

The safety and effectiveness of vepdegestrant in pediatric patients have not been established

Geriatric Use

Of 313 patients who received vepdegestrant in the VERITAC-2 study, 39% were 65 years of age or older and 13% were 75 years of age or older.1 No overall differences in safety or effectiveness of vepdegestrant were observed between patients 65 years of age or older compared to younger patients.1 There is an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or effectiveness.1

Common Adverse Effects

Most common (≥10%) adverse reactions with vepdegestrant, 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.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Strong CYP3A Inhibitors: Avoid concomitant use with strong CYP3A inhibitors.1 If concomitant use cannot be avoided, reduce vepdegestrant dosage.1
• Strong CYP3A Inducers: Avoid concomitant use with strong CYP3A inducers.1 If concomitant use cannot be avoided, increase vepdegestrant dosage.1
• Certain P-gp Substrates: Avoid concomitant use with certain P-gp substrates where minimal increases in concentration may lead to serious adverse reactions.1
• Certain UGT1A9 Substrates: Refer to the Prescribing Information for UGT1A9 substrates where minimal increases in concentration may lead to serious adverse reactions.1

Actions

Mechanism of Action

Vepdegestrant is a heterobifunctional protein degrader that binds to estrogen receptor (ER) and the E3 ligase cereblon (CRBN).1 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.1

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.1

Vepdegestrant is a small molecule comprised of an estrogen receptor binding domain joined by a linker to an E3 ligase binding domain.1

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).1
• Inform patients that vepdegestrant can cause QTc interval prolongation, which may increase the risk of Torsade de Pointes, other ventricular arrhythmias, and sudden death.1 Advise patients or caregivers of the signs or symptoms associated with the clinical consequences of QTc interval prolongation and to seek immediate medical attention if these are suspected or develop.1 Instruct patients to consult with their healthcare provider prior to taking other drugs that cause QTc interval prolongation with vepdegestrant.1
• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1 Advise females to inform their healthcare provider of a known or suspected pregnancy.1 Advise females of reproductive potential to use effective contraception during treatment with vepdegestrant and for 2 weeks after the last dose.1 Advise male patients with female partners of reproductive potential to use effective contraception during treatment with vepdegestrant and for 2 weeks after the last dose.1
• Advise women not to breastfeed during treatment with vepdegestrant and for 2 weeks after the last dose.1
• Advise males and females of reproductive potential that vepdegestrant may impair fertility.1
• Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.1 Inform patients to avoid St. John's wort, grapefruit, or grapefruit juice while taking vepdegestrant.1
• Advise patients to take vepdegestrant with food, how to make up for missed or vomited dose, and to swallow tablet(s) whole without chewing, crushing, dissolving or splitting the tablet.1

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Only references cited for selected revisions after 1984 are available electronically.

1. Arvinas Operations, Inc. VEPPANU (vepdegestrant) ORAL prescribing information. 2026 May.