Pharmacist's Application to Practice: Sevabertinib

FDA grants accelerated approval to sevabertinib for non-squamous non-small cell lung cancer

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What is the role of sevabertinib in in the treatment of adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) tyrosine kinase domain (TKD) activating mutations?

• Human epidermal growth factor 2 (HER2) has been recognized in recent years as a potential oncogenic driver and therapeutic target in non-squamous non-small cell lung cancer (NSCLC). Alterations in HER2 in NSCLC include gene mutation, gene amplification, and protein expression.¹
• HER2 gene mutations occur in approximately 4% of NSCLC cases and are predominantly mutually exclusive with other oncogenic drivers.² These mutations are more prevalent in females, non-smokers, and adenocarcinoma in histology, with exon 20 insertions in the tyrosine kinase domain (TKD) being the most common alteration.^3,4
• The landscape of HER2-targeted therapies has evolved in recent years. In 2022, trastuzumab-deruxtecan, an intravenous antibody-drug conjugate, became the first targeted therapy that was approved for the treatment of patients with NSCLC with HER2 overexpression.⁵ More recently in 2025, zongertinib, an oral HER2-targeted irreversible tyrosine kinase inhibitor (TKI) became the second agent approved in this setting and the first oral option which may be preferred for appropriate patients.⁶
• Sevabertinib (Hyruno) is an oral reversible kinase inhibitor of HER2 and exhibits activity against epidermal growth factor receptor (EGFR) mutations, while sparing wild-type EGFR. It is FDA approved for use in non-squamous NSCLC whose tumors have HER2 activating mutations.⁷
• EGFR, also known as HER1, belongs to same ErbB (HER) family of receptor tyrosine kinases as HER2. These receptors can interact through dimerization to drive tumor cell signaling. The heterodimerization of EGFR with HER2 induces a more potent signaling than EGFR homodimerization which leads to enhanced activation of proliferative and survival pathways.⁸
• Zongertinib differs mechanistically from sevabertinib in that it is designed to spare EGFR, whereas sevabertinib targets both EGFR and HER2. While this dual activity may have potential advantages, there is an increased risk of EGFR-related toxicities.⁹
• Sevabertinib accelerated drug approval was based on the SOHO-01 trial (NCT05099172), a phase 1-2, open-label, multicenter, dose-escalation, multicohort trial conducted in patients with locally advanced or metastatic NSCLC that harbored mutations in HER2 or EGFR.⁹
• A total of 209 patients with HER2-mutated NSCLC received sevabertinib 20 mg twice daily in the SOHO-01 trial from 2021-2024 across three cohorts: previously treated patients with no prior HER2-targeted therapy (group D), patients who had prior HER2-targeted antibody-drug conjugates (group E), and treatment naive patients (group F). An additional cohort assessed sevabertinib 10 mg twice daily (group D1).⁹
• The dose-escalation phase included patients with any EGFR or HER2 mutation and determined sevabertinib at a dose of 20 mg twice daily was considered to achieve a balance between the highest predicted benefit and an acceptable safety profile.⁹
• The primary outcome of the extension phase, objective response, was observed in 64% of patients in group D, 38% of patients in group E, 71% of group F, and 36% of group D1.⁹
• The most common adverse reactions reported amongst the different cohorts were diarrhea (84%-91%), rash (47%-51%), and paronychia (22%-29%). Dose reductions due to drug-related adverse events occurred in a total of 58 (28%) patients across the different cohorts.⁹

What role can the pharmacist play in the management of patients on sevabertinib?

• Dosing and Administration⁷
  • Recommended dose of sevabertinib
    • 20 mg orally twice daily with food, until disease progression or unacceptable toxicity
• Renal Impairment⁷
  • No renal dose adjustments mentioned in the package insert.
  • eGFR <30 ml/min: has not been studied.
• Hepatic Impairment⁷
  • No hepatic dose adjustments mentioned in the package insert
  • Moderate to severe hepatic impairment: has not been studied.
• Metabolism and Drug Interactions⁷
  • Sevabertinib is a substrate of BCRP, CYP3A4 (Major), P-glycoprotein (Minor).
  • Sevabertinib inhibits BCRP, P-glycoprotein, and is a weak CYP3A4 inhibitor.
  • Avoid concurrent administration with strong CYP3A inhibitors. If co-administration with strong CYP3A inhibitors is unavoidable, the dose should be adjusted as follows:
    • If current dosage 20 mg twice daily: Recommended dosage of 10 mg twice daily
    • If current dosage 10 mg twice daily: Recommended dosage of 10 mg once daily
    • If current dosage 10 mg once daily: Withhold sevabertinib until strong CYP3A inhibitor is discontinued
  • Close monitoring and/or dose adjustments may be warranted for certain P-gp and CYP3A4 substrates with a narrow therapeutic index
• Dose Modifications for Adverse Reactions

• • Diarrhea
    • Intolerable Grade 2 or 3:
      • Interrupt therapy until recovery to Grade ≤ 1
      • Resume therapy at the same dose or the next lower dose
      • For recurrence, resume therapy at the next lower dose
    • Intolerable Grade 4: Permanently discontinue therapy
  • Hepatotoxicity
    • Grade 2, 3 or 4 ALT and/or AST without increased total bilirubin or Grade 3 total bilirubin:
      • Interrupt therapy until recovery to Grade ≤ 1 or baseline
      • Resume therapy at the next lower dose
    • ALT or AST ≥ 3x ULN with total bilirubin ≥ 2x ULN or Grade 4 total bilirubin: Permanently discontinue therapy
  • Interstitial Lung Disease/Pneumonia
    • Any Grade: Permanently discontinue therapy
  • Ocular toxicity
    • Grade 2:
      • Interrupt therapy until recovery to Grade ≤ 1
      • Resume therapy at the next lower dose
      • For recurrence, permanently discontinue therapy
    • Grade 3 or 4: Permanently discontinue therapy
  • Pancreatic Enzyme Elevation
    • Grade 3:
      • Interrupt therapy until recovery to Grade ≤ 2 or baseline
      • Resume therapy at the next lower dose
    • Grade 4: Permanently discontinue therapy
  • Other Adverse Reactions
    • Intolerable or recurrent Grade 2 or Grade 3:
      • Interrupt therapy until recovery to Grade ≤ 1
      • Resume therapy at the same dose or the next lower dose
      • For recurrence, resume therapy at the next lower dose
    • Grade 4: Permanently discontinue therapy
• Monitoring⁷
  • Prior to initiation:
    • LFTs (ALT, AST, and total bilirubin) at baseline, every 2 weeks during the first month, and then monthly thereafter as clinically indicated.
    • Amylase/lipase at baseline and routinely during treatment.
    • Verify pregnancy status in patients who could become pregnant.
  • Patients who develop new or worsening ocular symptoms should be promptly referred to an ophthalmologist.
  • Monitor for new/worsening shortness of breath or cough. Sevabertinib should be discontinued in patients who develop pneumonitis/interstitial lung disease.
  • Advise patients who could become pregnant and patients with partners who could become pregnant to use effective contraception during treatment and for 1 week after the last sevabertinib dose.
  • Refer to the package label for additional information on when to hold sevabertinib, dose adjustments, and when to consider discontinuation due to toxicity.

Clinical Pearls

• Sevabertinib is supplied as 10 mg tablets and should be swallowed whole (do not cut, crush, or chew tablets). Tablets are packaged in a child-resistant container and should be stored in original container at room temperature.⁷
• Advise patients to administer a missed dose as soon as they remember prior to their next scheduled dose, but to not administer 2 doses at the same time to make up for a missed dose. If the dose is vomited, do not re-dose, and administer the next dose at the regularly scheduled time.⁷
• Co-pay assistance program available through Bayer HealthCare Pharmaceuticals.¹⁰
• As of May 18, 2026, first-line use of sevabertinib in ERBB2 mutated NSCLC is under FDA priority review based on results of the SOHO-1 trial if approved, sevabertinib would be the second oral tyrosine kinase inhibitor approved in ERBB2/HER2 mutated non-squamous, non-small cell lung cancer along with zongertinib.¹¹