FDA Expands Sevabertinib Approval to Frontline HER2-Mutant NSCLC

Sevabertinib (Hyrnuo; Bayer Healthcare Pharmaceuticals Inc.) has received expanded accelerated approval for 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-authorized test, regardless of prior treatment, the FDA announced.¹ The kinase inhibitor was previously approved only for patients with these HER2 mutations who had already received prior systemic therapy; this decision extends approval into the frontline setting for treatment-naive patients.^1,2

Trial Data Show a 75% Response Rate in Treatment-Naive Patients

The expanded approval is based on efficacy data from SOHO-01 (NCT05099172), an open-label, single-arm, multicenter, multicohort trial. HER2 (ERBB2) activating mutations were determined in tumor tissue or plasma by local laboratories before enrollment.¹

Among 69 treatment-naive patients with HER2 TKD–mutated NSCLC, the confirmed objective response rate (ORR), assessed by blinded independent central review using RECIST v1.1, was 75% (95% CI, 64-85). Of the patients who responded, 73% had a duration of response of at least 6 months, and 38% maintained a response for 12 months or longer.

That builds on the drug's original approval data: among 70 patients naive to HER2-targeted therapy, sevabertinib produced a 71% ORR (95% CI, 59-82) with a median duration of response of 9.2 months, while a separate group of 52 patients who had already received a prior HER2-targeted therapy saw a lower ORR of 38% (95% CI, 25-53).²

Drug-related adverse events occurred in 96% of participants, with 31% reporting an event of grade 3 or higher; diarrhea was the most frequently reported adverse event, and 3% of patients discontinued treatment because of drug-related toxicity.

Warnings Cover Diarrhea, Liver and Cardiac Toxicity, and More

Prescribing information for sevabertinib includes warnings and precautions for diarrhea, hepatotoxicity, interstitial lung disease/pneumonitis, left ventricular dysfunction, ocular toxicity, pancreatic enzyme elevation, and embryo-fetal toxicity.¹ The recommended dose remains 20 mg orally twice daily with food, continued until disease progression or unacceptable toxicity.

The FDA reviewed the application under Project Orbis, an Oncology Center of Excellence initiative enabling concurrent submission and review among international regulators; for this review, the FDA collaborated with the United Kingdom's Medicines and Healthcare products Regulatory Agency, with reviews continuing at other participating agencies. Bayer's voluntary Assessment Aid submission was also used to facilitate the FDA's review.

The application received priority review, and sevabertinib previously earned breakthrough therapy and orphan drug designations. Its original approval in November 2025 marked the drug's first authorization worldwide.²

HER2-Mutant NSCLC Remains a Small but Growing Treatment Category

A 2026 analysis of a US clinico-genomic database of patients with advanced or metastatic NSCLC found that 3.8% carried a HER2 mutation, with 1.8% considered an oncogenic driver; patients with HER2 tyrosine kinase domain mutations tended to be younger, female, and never-smokers.³ Until this approval, no HER2-directed therapy had been approved for first-line use in NSCLC, and patients were generally treated with platinum-based chemotherapy, with or without immunotherapy.

The antibody-drug conjugate trastuzumab deruxtecan and the kinase inhibitor zongertinib have both received accelerated approval for previously treated HER2-mutant NSCLC, alongside sevabertinib's original indication, making today's frontline expansion the first HER2-directed option available to treatment-naive patients in this molecularly defined subgroup.^1,3

References

1. FDA grants accelerated approval to sevabertinib for locally advanced or metastatic non-squamous non-small cell lung cancer. News release. FDA. September 9, 2026. Accessed September 9, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sevabertinib-locally-advanced-or-metastatic-non-squamous-non-small

2. FDA approves sevabertinib for nonsquamous NSCLC. AJMC^®. November 19, 2025. Accessed September 9, 2026. https://www.ajmc.com/view/fda-approves-sevabertinib-for-nonsquamous-nsclc

3. Lovly CM, Baik C, Nagasaka M, et al. Real-world patient characteristics, mutational landscape, and outcomes in advanced/metastatic HER2-mutant non–small cell lung cancer. JCO Precis Oncol. 2026;10(6):e2501272. doi:10.1200/PO-25-01272