AHFS Class:

• Antineoplastic Agents 10:00

Brands:

• Hyrnuo^®

Generic Name(s):

• Sevabertinib

Sevabertinib, a kinase inhibitor of human epidermal growth factor receptor 2 (HER2), is an antineoplastic agent.1

Sevabertinib has the following uses:

Sevabertinib is indicated for the treatment of adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have HER2 ( ERBB2 ) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.1

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR).1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1

General

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

Tablets: 10 mg of sevabertinib.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Select patients for treatment with sevabertinib based on the presence of HER2 (ERBB2) TKD activating mutations in tumor specimens.1
• Recommended dosage is 20 mg orally twice daily with food until disease progression or unacceptable toxicity.1
• Swallow tablets whole.1 Do not cut, crush, or chew tablets.1
• See Full Prescribing Information for dosage modification recommendations for adverse reactions and for concomitant use with strong CYP3A inhibitors.1

Contraindications

None.1

Warnings/Precautions

Diarrhea

Sevabertinib can cause severe diarrhea that can lead to dehydration and electrolyte imbalances.1 In the pooled safety population, diarrhea was reported in 86% of patients who received sevabertinib including Grade 3 in 15%.1 The median time to first onset of any grade diarrhea was four days.1 Dosage interruptions occurred in 15% of patients, and dose reductions occurred in 12% of patients.1

At the first sign of diarrhea or increased bowel movement frequency, instruct patients to start an antidiarrheal treatment (e.g., loperamide and to increase their fluid and electrolyte intake.1 Interrupt, reduce the dose, or permanently discontinue sevabertinib based on severity.1

Hepatotoxicity

Sevabertinib can cause severe hepatotoxicity characterized by elevations of liver function tests.1 In the pooled safety population, based on adverse reaction data, hepatotoxicity occurred in 24% of patients treated with sevabertinib including 3% Grade 3.1 Based on laboratory data, 35% of patients treated with sevabertinib experienced increased alanine aminotransferase (ALT), including 2.3% Grade 3.1 Increased aspartate aminotransferase (AST) occurred in 35% of patients treated with sevabertinib, including 2.3% Grade 3.1 Increased bilirubin occurred in 12% of patients treated with sevabertinib.1 The median time to first onset of AST or ALT elevation was 1.4 (range 0.2 to 14.5) months.1 Sevabertinib was interrupted for an adverse reaction of hepatotoxicity in 4.1% of patients, the dose was reduced in 4.1% and permanently discontinued in 0.4%.1

Monitor liver function tests including ALT, AST, and total bilirubin at baseline prior to the first administration of sevabertinib, every 2 weeks for the first month, and then monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations.1 Interrupt, reduce the dose, or permanently discontinue sevabertinib based on the severity of the adverse reaction.1

Interstitial Lung Disease/Pneumonitis

Sevabertinib can cause severe interstitial lung disease (ILD)/pneumonitis.1 In the pooled safety population ILD/pneumonitis occurred in two patients (0.7%) treated with sevabertinib, including 0.4% Grade 3.1 One patient required interruption of sevabertinib.1

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever).1 Discontinue sevabertinib upon confirmation of ILD/pneumonitis.1

Ocular Toxicity

Sevabertinib can cause ocular toxicity.1 In the pooled safety population, ocular toxicity occurred in 14% of patients treated with sevabertinib, including 11% Grade 1, 2.6% Grade 2 and 0.4% Grade 3 (one case of corneal epithelial microcysts with temporary unilateral blindness).1

Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist.1 Interrupt, reduce the dose or permanently discontinue sevabertinib based on severity. 1

Pancreatic Enzyme Elevation

Sevabertinib can cause elevations of amylase and lipase levels.1 In the pooled safety population, based on laboratory data, increased amylase occurred in 32% of patients treated with sevabertinib, including 3.2% Grade 3 or 4.1 Increased lipase elevation occurred in 40% of patients treated with sevabertinib, including 10% Grade 3 or 4.1 Two patients (0.7%) required interruption of sevabertinib due to increased lipase and 3 (1.1%) required interruption of the drug due to increased amylase.1 The median time to onset of increased amylase/lipase was 1.4 months (range 0.2 to 17 months).1

Monitor amylase and lipase regularly during treatment with sevabertinib.1 Interrupt, reduce the dose, or permanently discontinue sevabertinib based on severity. 1

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, sevabertinib can cause fetal harm when administered to a pregnant woman.1 In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on AUC at the clinical dose of 20 mg twice daily.1 Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality.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 sevabertinib and for 1 week after the last dose.1 Advise male patients with female partners of reproductive potential to use effective contraception during treatment with sevabertinib and for 1 week after the last dose.1

Specific Populations

Pregnancy

Based on findings from animal studies and its mechanism of action, sevabertinib can cause fetal harm when administered to a pregnant woman.1 There are no available data on the use of sevabertinib in pregnant women to inform a drug-associated risk.1 In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on AUC at the clinical dose of 20 mg twice daily.1 Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality.1 Advise pregnant women 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 sevabertinib or its metabolites in human milk or their effects on a breastfed child or on milk production.1 In rats, sevabertinib or its metabolites are excreted in milk.1 Because of the potential for serious adverse reactions in breastfed children from sevabertinib, advise women not to breastfeed during treatment with sevabertinib and for 1 week after the last dose.1

Females and Males of Reproductive Potential

Sevabertinib can cause fetal harm when administered to a pregnant woman.1

Verify pregnancy status in females of reproductive potential prior to initiating sevabertinib.1

Advise females of reproductive potential to use effective contraception during treatment with sevabertinib and for 1 week after the last dose.1

Advise males with female partners of reproductive potential to use effective contraception during treatment with sevabertinib and for 1 week after the last dose.1

Pediatric Use

The safety and effectiveness of sevabertinib have not been established in pediatric patients.1

Geriatric Use

Of the 268 patients with locally advanced or metastatic NSCLC harboring HER2 activating mutations who received sevabertinib at 20 mg twice daily in the SOHO-01 study, 43% were 65 years of age and older and 13% were 75 years of age and older.1 No overall differences in effectiveness were observed between these older and younger patients.1 Grade 3 diarrhea was observed in 23% of patients ≥75 years of age and 14% of patients <75 years of age.1

Common Adverse Effects

• Most common adverse reactions (>20%): diarrhea, rash, paronychia, stomatitis, and nausea.1
• Most common Grade 3 or 4 laboratory abnormalities (≥2%): decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST.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 sevabertinib dosage.1
• Moderate CYP3A Inhibitors: Monitor patients for increased sevabertinib-associated adverse reactions.1
• Strong and Moderate CYP3A Inducers: Avoid concomitant use with strong or moderate CYP3A inducers.1
• Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates where minimal increases in concentration may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information of the CYP3A substrate.1
• Certain P-gp Substrates: Refer to the Prescribing Information for P-gp substrates where minimal increases in concentration may lead to serious adverse reactions.1

Actions

Mechanism of Action

Sevabertinib is a reversible kinase inhibitor of human epidermal growth factor receptor 2 (HER2).1 It also exhibits activity against epidermal growth factor receptor (EGFR).1

In vitro, sevabertinib inhibited the phosphorylation of HER2 and downstream signaling in cancer cells with HER2 alterations and proliferation of cancer cells overexpressing wild-type HER2 or harboring HER2 mutations.1

In vivo, sevabertinib demonstrated antitumor activity in subcutaneous mouse xenograft models derived from human NSCLC tumors harboring an activating HER2 exon 20 mutation.1

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).1
• Inform patients that sevabertinib can cause severe diarrhea.1 At the first sign of diarrhea or increased bowel movement frequency, instruct patients to start an antidiarrheal treatment (e.g., loperamide), to increase their fluid and electrolyte intake, and to immediately contact their healthcare provider.1
• Inform patients that sevabertinib can cause severe hepatotoxicity characterized by elevations of liver function tests.1 Inform patients that they will need to undergo lab tests to monitor hepatic function.1 Advise patients to immediately contact their healthcare provider for signs and symptoms of hepatotoxicity. 1
• Inform patients that sevabertinib can cause severe ILD/pneumonitis.1 Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms. 1
• Inform patients that sevabertinib can cause ocular toxicity.1 Advise patients to immediately contact their healthcare provider for new or worsening ocular symptoms. 1
• Inform patients that sevabertinib can cause pancreatic enzyme elevation.1 Inform patients that they will need to undergo lab tests to monitor pancreatic function.1 Advise patients to immediately contact their healthcare provider for signs and symptoms associated with pancreatic enzyme elevation. 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 sevabertinib and for 1 week after the last dose.1
• Advise male patients with female partners of reproductive potential to use effective contraception during treatment with sevabertinib and for 1 week after the last dose.1
• Advise women not to breastfeed during treatment with sevabertinib and for 1 week after the last dose.1
• Instruct patients to take sevabertinib twice daily with food.1 Each tablet should be swallowed whole. 1
• Instruct patients that if a dose of sevabertinib is missed to take the missed dose as soon as they remember prior to the next scheduled dose.1 Advise patients not to take two doses together to make up for a missed dose. 1
• Instruct patients that if a dose of sevabertinib is vomited not to take an additional dose but to take the next dose at the next scheduled time. 1
• Advise patients and caregivers to inform their healthcare provider 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 sevabertinib.1

Additional Information

AHFS first Release^™. 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.

1. Bayer HealthCare Pharmaceuticals Inc. HYRNUO^® (SEVABERTINIB) ORAL prescribing information. 2025 Dec. [Web]