FDA Grants Priority Review to Frontline Sevabertinib in HER2-Mutant NSCLC

The US FDA has accepted a supplemental new drug application (sNDA) and granted priority review status to the small molecule tyrosine kinase inhibitor sevabertinib (Hyrnuo) for the first-line treatment of adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2/ERBB2) tyrosine kinase domain (TKD) activating mutations.¹The priority review designation aims to expedite the evaluation of therapeutics that offer substantial therapeutic improvements over existing modalities for serious medical conditions, with a target decision date within 6 months.

The regulatory submission is supported by clinical evidence from Cohort F of the ongoing phase 1/2 SOHO-01 study (NCT05099172), which evaluates the oral therapy in treatment-naive patients. If approved, the decision would expand the clinical utility of sevabertinib into the frontline setting. The agent previously received accelerated approval from the FDA in November 2025 for patients with locally advanced or metastatic nonsquamous NSCLC harboring HER2 TKD activating mutations whose disease progressed following prior systemic therapy.² In January this year, the FDA granted breakthrough therapy designation to sevabertinib in the first-line population.³

Activating HER2 mutations occur in approximately 2% to 4% of advanced NSCLC cases, and the disease carries a poor prognosis.⁴Because nearly 80% of patients with NSCLC present with or progress to advanced stages at initial diagnosis, managing this population remains highly challenging.⁵

Mechanism of Action

Sevabertinib functions as an oral, reversible, small molecule tyrosine kinase inhibitor.It selectively targets mutated human HER2, including exon 20 insertions and specific point mutations. Additionally, the agent inhibits epidermal growth factor receptors (EGFR), displaying therapeutic selectivity for mutated variants over wild-type EGFR. By reversibly binding to these enzymes, the molecule disrupts downstream signaling pathways crucial for oncogenic cell proliferation and survival, minimizing wild-type EGFR-mediated toxicities.¹

Clinical Trial Evidence

The ongoing SOHO-01 trial is an open-label, multi-cohort, multicenter study designed to determine the safety, tolerability, and preliminary efficacy of sevabertinib.The primary end points for the trial include treatment-emergent adverse events (AEs), maximum tolerated dose, dose-limiting toxicities, and the objective response rate (ORR) determined by blinded independent central review using RECIST v1.1 criteria.¹ Secondary end points encompass the recommended phase 2 dose, disease control rate, duration of response (DOR), progression-free survival, and overall survival.

Data from the previously treated patient cohorts in SOHO-01, which formed the basis of the November 2025 accelerated approval, demonstrated significant antitumor activity.In patients who were naive to prior HER2-targeted therapies (n = 70), sevabertinib elicited a confirmed ORR of 71% (95% CI, 59%-82%) and a median DOR of 9.2 months (95% CI, 3-15.0). Within a separate cohort of patients previously treated with HER2-targeted antibody-drug conjugates (n = 52), the agent achieved an ORR of 38% (95% CI, 25%-53%) and a median DOR of 7.0 months (95% CI, 5.6-not evaluable).

Safety and Monitoring Profile

Pooled safety analysis from the clinical development of sevabertinib indicates a manageable safety profile, though close monitoring is required for certain toxicities.The most common AEs occurring in more than 20% of patients include diarrhea, rash, paronychia, stomatitis, and nausea. Discontinuation of therapy due to adverse events occurred in 3.7% of the clinical cohort. Current prescribing information includes explicit warnings and precautions regarding the clinical management of diarrhea, hepatotoxicity, interstitial lung disease or pneumonitis, ocular toxicity, pancreatic enzyme elevation, and embryo-fetal toxicity.

Further validation of sevabertinib in the frontline setting is currently underway. The phase 3 SOHO-02 trial (NCT06452277) is actively evaluating the safety and efficacy of sevabertinib compared with standard-of-care systemic therapy in untreated patients with advanced HER2-mutated NSCLC.

REFERENCES

1. U.S. FDA Grants Priority Review to Supplemental New Drug Application for HYRNUO® (sevabertinib) Under Investigation as a First-Line Treatment of HER2-Mutated Non-Small Cell Lung Cancer. News release. Bayer. May 18, 2026. Accessed May 19, 2026. https://tinyurl.com/4sysyh9s

2. FDA grants accelerated approval to sevabertinib for non-squamous non-small cell lung cancer. News release. US FDA. November 19, 2025. Accessed May 19, 2026. https://tinyurl.com/wyesray4
3. Bayer receives breakthrough therapy designation in the U.S. and China for sevabertinib as a first-line treatment for patients with HER2-mutant non-small cell lung cancer. News release. Bayer. January 6, 2026. Accessed May 19, 2026. https://tinyurl.com/5hbten53

4. Okwonna C & Suwaidan AA. Exploring the Prospects of HER2-Directed Therapies for Patients With Advanced Lung Cancer. ASCO Daily News. April 2, 2026. Accessed May 19, 2026. https://tinyurl.com/4wpv4xj3

5. Ozkaya S, Findik S, Dirican A, Atici AG. Long-term survival rates of patients with stage IIIB and IV non-small cell lung cancer treated with cisplatin plus vinorelbine or gemcitabine. Exp Ther Med. 2012 Dec;4(6):1035-1038. doi: 10.3892/etm.2012.714. Epub 2012 Sep 18. PMID: 23226770; PMCID: PMC3494120.