Sevabertinib, a small molecule kinase inhibitor of human epidermal growth factor receptor 2 ( HER2 ), is an antineoplastic agent.1
Sevabertinib is used for adults with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumors have human epidermal growth factor receptor 2 ( HER2 ; encoded by erb-b2 receptor tyrosine kinase 2 [ ERBB2 ]) activating mutations detected by an FDA-approved test and who have received prior systemic therapy.1 Information on FDA-approved tests is available at [Web].1
The current indication for sevabertinib is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR).1, 2 Continued approval may depend on verification and further description of clinical benefit in a confirmatory trial.1, 2 Sevabertinib has been designated an orphan drug by FDA for the treatment of NSCLC with HER2 ( ERBB2) mutations.3
Efficacy and safety of sevabertinib were evaluated in SOHO-01, an open-label, single-arm, multicenter, multi-cohort, phase 1/2 study in patients with locally advanced or metastatic non-squamous NSCLC with HER2 ( ERBB2 ) activating mutations.1, 2, 4 Eligible patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, HER2- activating mutations identified by local tumor tissue or plasma testing, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1, 4 Patients with treated, stable, and asymptomatic brain metastases were eligible, while patients with symptomatic CNS metastases, clinically significant cardiac disease, or a history of steroid-dependent interstitial lung disease/pneumonitis were excluded.1, 2, 4 Patients received sevabertinib 20 mg orally twice daily until disease progression or unacceptable toxicity.1, 2, 4 The major efficacy outcome measures were confirmed ORR and DOR, as assessed by blinded independent central review using RECIST version 1.1.1, 2, 4 The efficacy population included two previously-treated cohorts with advanced non-squamous NSCLC with HER2 tyrosine kinase domain-activating mutations: patients who had not received prior HER2 mutation-targeted therapy and patients who had previously received HER2 -targeted antibody-drug conjugate therapy.1, 2
Among the 70 patients who had not received prior HER2 -directed therapy, the median age was 59 years (range, 29‒77 years); 67% were female, 70% were Asian, 23% were White, 1.4% were Black or African American, and 2.9% were Hispanic or Latino.1, 2 All patients had adenocarcinoma histology; 91% had stage IV disease, 20% had stable brain metastases, and 70% had a Y772_A775dup (YVMA) exon 20 insertion.1 Additionally, 69% of patients were never-smokers.1, 2 The median number of prior therapies was 1 (range, 1 to 8); 94% of patients received prior platinum-based chemotherapy, 71% received prior immunotherapy, and 69% received both platinum-based chemotherapy and immunotherapy.1 The confirmed ORR in this cohort was 71%; 2.9% of patients had a complete response and 69% had a partial response.1, 2 The median DOR was 9.2 months, with 54% of responders having an observed DOR ≥6 months and 18% having an observed DOR ≥12 months.1, 2
Among the 52 patients who received prior systemic treatment with platinum-based chemotherapy and a HER2 -targeted antibody-drug conjugate therapy, the median age was 65 years (range, 35‒91 years); 67% were female, 62% were Asian, 27% were White, 6% were Black or African American, and 1.9% were Hispanic or Latino.1, 2 All patients had adenocarcinoma histology; 85% had stage IV disease, 29% had stable brain metastases, and 77% had a Y772_A775dup (YVMA) exon 20 insertion.1 Additionally, 65% of patients were never-smokers.1, 2 The median number of prior therapies was 2 (range, 1 to 8); 77% of patients received prior platinum-based chemotherapy, 56% received prior immunotherapy, and 56% received both platinum-based chemotherapy and immunotherapy.1 The confirmed ORR in this cohort was 38%; 6% of patients had a complete response and 33% had a partial response.1, 2 The median DOR was 7 months, with 60% of responders having an observed DOR ≥6 months and 10% having an observed DOR ≥12 months.1, 2
The American Society of Clinical Oncology (ASCO) guidelines on management of stage IV NSCLC with driver alterations addresses treatment decisions based on HER2 overexpression.5 For patients with stage IV NSCLC harboring HER2 mutations, ASCO recommends HER2 -targeted therapy such as trastuzumab deruxtecan.5 Sevabertinib is not discussed since the drug was approved after guideline publication.5
Administer orally with food.1
Sevabertinib is available as a 10-mg tablet.1
Swallow sevabertinib tablets whole with water; do not split, crush, or chew.1
If a dose is missed, take it as soon as remembered unless it is almost time for the next dose.1 Do not take 2 doses at once.1
If vomiting occurs after administration of sevabertinib tablets, do not take an additional dose; take the next dose at the scheduled time.1
Store tablets at 20-25°C; excursions permitted to 15-30°C.1
The recommended adult dosage of sevabertinib for the treatment of 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 is 20 mg orally twice daily until disease progression or unacceptable toxicity.1
Dosage Modification for Adverse Reactions
If adverse events occur during therapy, temporary interruption, dosage reduction, and/or discontinuance of sevabertinib may be necessary.1
For the first dosage reduction, reduce the sevabertinib dosage to 10 mg twice daily.1
For the second dosage reduction, reduce the dosage to 10 mg once daily.1
Permanently discontinue sevabertinib in patients who are unable to tolerate a dosage of 10 mg once daily.1
The recommended dosage modifications of sevabertinib for adverse reactions are present in Table 1.1
Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
Diarrhea | Intolerable Grade 2 or Grade 3 | Interrupt until recovery to Grade ≤1. Resume at the same dose or the next lower dosage. For recurrence, resume at the next lower dosage. |
Grade 4 | Permanently discontinue. | |
Hepatotoxicity | Grade 2, 3, or 4 ALT and/or AST without increased total bilirubin OR Grade 3 total bilirubin | Interrupt until recovery to Grade ≤1 or baseline. Resume at the next lower dosage. |
ALT or AST ≥ 3 times the upper limit of normal (ULN) with total bilirubin ≥2 times ULN OR Grade 4 total bilirubin | Permanently discontinue. | |
ILD/ Pneumonitis | Any Grade | Permanently discontinue. |
Ocular Toxicity | Grade 2 | Interrupt until recovery to Grade ≤1. Resume at next lower dosage. For recurrence, permanently discontinue. |
Grade 3 or Grade 4 | Permanently discontinue. | |
Pancreatic Enzyme Elevation | Grade 3 | Interrupt until recovery to Grade ≤2 or baseline. Resume at the next lower dosage. |
Grade 4 | Permanently discontinue. | |
Other Adverse Reactions | Intolerable or recurrent Grade 2 or Grade 3 | Interrupt until recovery to Grade ≤1. Resume at the same dosage or the next lower dosage. For recurrence, resume at the next lower dosage. |
Grade 4 | Permanently discontinue. |
Dosage Modifications for Concomitant Use with Cytochrome P-450 3A Inhibitors
Avoid current use of sevabertinib with strong cytochrome P-450 (CYP) 3A inhibitors.1
If concurrent use cannot be avoided, reduce the sevabertinib dosage from 20 mg twice daily to 10 mg twice daily or from 10 mg twice daily to 10 mg once daily; withhold sevabertinib therapy in patients receiving a dosage of 10 mg once daily until the strong CYP3A inhibitor is discontinued.1
After the CYP3A inhibitor has been discontinued for 3‒5 elimination half-lives, resume the sevabertinib dosage used before initiating the inhibitor.1
The manufacturer makes no specific dosage recommendations for patients with mild hepatic impairment.1 The effects of moderate to severe hepatic impairment have not been studied.1
The manufacturer makes no specific dosage recommendations for patients with mild or moderate renal impairment.1 The effects of severe renal impairment or end-stage renal disease have not been studied.1
The manufacturer makes no recommendation for dosage adjustment in geriatric patients.1
Sevabertinib may cause severe diarrhea, which may lead to dehydration and electrolyte imbalances.1 Diarrhea occurred in 86% of patients, including Grade 3 diarrhea in 15% of patients; the median time to first onset was 4 days.1 At the first sign of diarrhea or increased bowel movement frequency, patients should start antidiarrheal therapy, such as loperamide, and increase fluid and electrolyte intake.1 Based on severity, interrupt, reduce, or permanently discontinue sevabertinib.1
Sevabertinib can cause severe hepatotoxicity characterized by elevated liver function tests.1 Hepatotoxicity occurred in 24% of patients, including Grade 3 events in 3% of patients.1 ALT and AST elevations each occurred in 35% of patients, including Grade 3 elevations in 2.3% of patients; bilirubin elevations occurred in 12% of patients.1 The median time to first AST or ALT elevation was 1.4 months.1 Increased bilirubin occurred in 12% of patients.1 Monitor ALT, AST, and total bilirubin at baseline, every 2 weeks for the first month, and monthly thereafter as clinically indicated, with more frequent testing in patients who develop transaminase elevations.1 Based on severity, interrupt, reduce, or permanently discontinue sevabertinib.1
Sevabertinib can cause severe interstitial lung disease (ILD)/pneumonitis.1 ILD/pneumonitis occurred in 0.7% of patients, including Grade 3 events in 0.4% of patients.1 Monitor patients for new or worsening symptoms, such as dyspnea, cough, or fever.1 Permanently discontinue sevabertinib upon confirmation of ILD/pneumonitis.1
Sevabertinib can cause ocular toxicity.1 Ocular toxicity occurred in 14% of patients, including Grade 3 events in 0.4% of patients.1 Promptly refer patients with new or worsening eye symptoms to an ophthalmologist.1 Based on severity, interrupt, reduce, or permanently discontinue sevabertinib.1
Sevabertinib can cause elevations in amylase and lipase.1 Increased amylase occurred in 32% of patients, including Grade 3 or 4 elevations in 3.2% of patients; increased lipase occurred in 40% of patients, including Grade 3 or 4 elevations in 10% of patients.1 The median time to onset was 1.4 months.1 Monitor amylase and lipase regularly during treatment.1 Based on severity, interrupt, reduce, or permanently discontinue sevabertinib.1
Fetal/Neonatal Morbidity and Mortality
Based on animal studies and its mechanism of action, sevabertinib can cause fetal harm.1 Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1 Females of reproductive potential and male patients with female partners of reproductive potential should use effective contraception during treatment with sevabertinib and for 1 week after the last dose.1
Based on animal studies and its mechanism of action, sevabertinib can cause fetal harm when administered to a pregnant woman.1 There are no available data in pregnant women to inform a drug-associated risk.1 Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1
There are no data on the presence of sevabertinib or its metabolites in human milk, effects on a breastfed child, or effects on milk production.1 Because of the potential for serious adverse reactions, 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.1 Verify pregnancy status in females of reproductive potential before starting treatment.1 Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment with sevabertinib and for 1 week after the last dose.1
Safety and effectiveness of sevabertinib have not been established in pediatric patients.1
Among 268 patients who received sevabertinib, 43% were ≥65 years of age and 13% were ≥75 years of age.1 No overall differences in effectiveness were observed between older and younger patients; however, Grade 3 diarrhea occurred more often in patients ≥75 years of age than in those <75 years of age.1
Mild hepatic impairment had no clinically significant effect on sevabertinib pharmacokinetics.1 The effects of moderate or severe hepatic impairment on sevabertinib pharmacokinetics are unknown.1
Renal impairment with an estimated glomerular filtration rate (eGFR) 30 to <90 mL/min had no clinically significant effect on sevabertinib pharmacokinetics.1 The effects of severe renal impairment and end-stage renal disease on sevabertinib pharmacokinetics are unknown.1
Most common adverse reactions (>20%) include diarrhea, rash, paronychia, stomatitis, and nausea.1
Most common Grade 3 or 4 laboratory abnormalities (≥2%) include decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST.1
Sevabertinib is a substrate of cytochrome P450 (CYP) isoenzyme 3A4, a weak to moderate CYP3A inhibitor, a substrate and inhibitor of P-glycoprotein, and a substrate of breast cancer resistance protein (BCRP).1
Sevabertinib inhibits CYP1A1 and 2C8 but does not inhibit 2A6, 2C9, 1A2, 2B6, 2D6, 2C19, or 2E1.1 Sevabertinib does not induce 1A2, 2B6, or 2C19.1
Sevabertinib inhibits multidrug and toxin extrusion protein (MATE) 1 and MATE2-K but does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, multidrug resistance-associated protein 2 (MRP2), organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, or OCT2.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concurrent use with strong CYP3A inhibitors may increase sevabertinib exposure and the potential for adverse reactions; avoid concurrent use.1 If concurrent use cannot be avoided, reduce the sevabertinib dosage and monitor the patient for adverse reactions.1 Concurrent use of sevabertinib with itraconazole, a strong CYP3A inhibitor, increased sevabertinib AUC 130% and maximum concentration by 60%.1 Monitor patients for adverse reactions with sevabertinib when used with a moderate CYP3A inhibitor.1
Concurrent use with strong or moderate CYP3A inducers may decrease sevabertinib exposure and effectiveness; avoid concurrent use.1 Concurrent use of sevabertinib with carbamazepine, a strong CYP3A inducer, decreased sevabertinib AUC by 79% and maximum concentration by 57%.1
Avoid concurrent use of sevabertinib with a CYP3A substrate when small increases in the concentration of the CYP3A substrate may lead to serious adverse reactions, unless otherwise recommended in the substrate Prescribing Information.1 Concurrent use of sevabertinib with midazolam, a CYP3A substrate, increased midazolam AUC 100% and maximum concentration by 80%.1
Sevabertinib inhibits CYP1A1 in vitro and may increase exposure to a CYP1A1 substrate, which may increase the risk of adverse reactions associated with the CYP1A1 substrate.1 Refer to the Prescribing Information for the CYP1A1 substrate.1
Drugs Affecting or Affected by Transport Systems
Sevabertinib, a P-glycoprotein inhibitor, may increase exposure to a P-glycoprotein substrate and increase the risk of adverse reactions associated with the P-glycoprotein substrate.1 Refer to the Prescribing Information for a P-glycoprotein substrate when small increases in the concentration of the P-glycoprotein substrate may lead to serious adverse reactions.1 Concurrent use of sevabertinib with dabigatran etexilate, a P-glycoprotein substrate, increased dabigatran etexilate AUC by 40%.1
Concurrent use of sevabertinib with rosuvastatin, a BCRP substrate, increased rosuvastatin AUC by 30% and maximum concentration by 40%.1
Drugs Affecting Gastric Acidity
Concurrent use of sevabertinib with esomeprazole, a proton pump inhibitor, did not affect sevabertinib pharmacokinetics.1
Sevabertinib is a reversible human epidermal growth factor receptor 2 ( HER2 ) kinase inhibitor with activity against epidermal growth factor receptor ( EGFR ).1 In preclinical studies, sevabertinib inhibited HER2 phosphorylation, downstream signaling, and proliferation in cancer cells with HER2 alterations.1 In vivo, sevabertinib demonstrated antitumor activity in non-small cell lung cancer (NSCLC) xenograft models with HER2 mutations.1
At the approved dosage, sevabertinib exposure increased dose proportionally across 10‒80 mg at steady state.1 Steady state was reached within 3 days, with AUC increasing approximately 70% and maximum concentration by 30%.1 After a single dose, the median time to maximum concentration was 2 hours (range 0.5‒8.2 hours).1 A high-fat meal decreased the maximum concentration by 56% and AUC by 28%, while a low-fat meal had no clinically significant effect.1 Sevabertinib has plasma protein binding of 95% and an effective half-life of approximately 8 hours.1 Sevabertinib is primarily metabolized by cytochrome P450 (CYP) 3A, with minor metabolism by CYP1A1 and glucuronidation.1 After a single oral radiolabeled 40-mg dose, 84% was recovered in feces and 10% in urine.1 No clinically significant pharmacokinetic differences were observed based on age, race, sex, body weight, smoking status, estimated glomerular filtration rate (eGFR) of 30 to <90 mL/minute, or mild hepatic impairment; effects of severe renal impairment, end-stage renal disease, and moderate or severe hepatic impairment are unknown.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Sevabertinib is available only from designated specialty pharmacies. Contact the manufacturer or consult the sevabertinib website ([Web]) for more information.1
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 10 mg | Hyrnuo® | Bayer HealthCare Pharmaceuticals |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions September 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Bayer HealthCare Pharmaceuticals Inc. HYRNUO® (SEVABERTINIB) ORAL prescribing information. 2025 Dec. [Web]
2. US Food and Drug Administration. Center for Drug Evaluations and Research Application Number: 219972Orig1s000 Multi-Discipline Review. Accessed 2026 June 26. [Web]
3. US Food and Drug Administration. Search orphan drug designations and approvals. Accessed 2026 June 26. [Web]
4. Le X, Kim TM, Loong HH, et al. Sevabertinib in advanced HER2-mutant non-small-cell lung cancer. N Engl J Med. 2025;393(18):1819-1832.
5. Reuss JE, Kuruvilla S, Ismaila N, et al. Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO living guideline, Version 2025.1. J Clin Oncol. 2025;43(24):e31-e44.