Sevabertinib Yields Antitumor Activity in Non–Small Cell Lung Cancer

Results from a phase 1/2 clinical trial (NCT05099172) show the safety and efficacy of sevabertinib (BAY2927088) in patients with non–small cell lung cancer (NSCLC) harboring HER2 or EGFR mutations.¹

Sevabertinib showed rapid, durable, and clinically meaningful antitumor activity, with high response rates in treatment-naive patients. Objective response rates (ORRs) varied among the cohorts; there was a 64% ORR in the pretreated, HER2 targeted therapy-naive patient cohort (95% CI, 53%–75%), a 38% ORR in the pretreated with HER2 antibody-drug conjugate (ADC) cohort (95% CI, 25%–52%), and a 71% ORR in treatment-naive patients (95% CI, 59%–81%). The median duration of response (DOR) for each respective cohort was 9.2 months vs 8.5 months vs 11 months. The median progression-free survival (PFS) for each respective cohort was 8.3 months vs 5.5 months, with immature data in the treatment-naive cohort. Patients with brain metastases showed similar ORRs compared with patients without brain metastases.

The most common adverse event (AE) was grade 1 or 2 diarrhea. Grade ≥3treatment-emergent AEs occurred in 31% of patients. Treatment discontinuation due to AEs occurred in 3% of patients. There were no cases of interstitial lung disease or pneumonitis, which is a known, serious risk associated with HER2-targeted therapies like ADCs in NSCLC.

“Lung cancer patients with tumors harboring HER2 exon 20 insertions currently have a poor prognosis and only limited options for targeted therapy,” said Siegel et al, authors of the study.¹ “Although trastuzumab deruxtecan (T-DXd, [Enhertu]) and zongertinib [Hernexeos] have received accelerated approval for the treatment of patients [with NSCLC] with HER2 exon 20 insertions, there is still a need for active and well-tolerated oral therapies for these patients.”

Patient Criteria

Patient inclusion criteria included, but were not limited to, having a documented histologically or cytologically confirmed locally advanced NSCLC unsuitable for definitive therapy, documented disease progression after treatment, adequate archival tumor tissue, and measurable disease by RECIST v1.1.²

Patient exclusion criteria included, but were not limited to, having received treatment with an EGFR tyrosine kinase inhibitor (TKI) ≤8 days or 5 times the terminal phase, elimination half-lives, whichever is shorter, prior to the first dose of study drug; treatment with a systemic anticancer treatment (excluding EGFR TKIs as described above) ≤14 days prior to the first dose of study drug; and radiation therapy, stereotactic radiosurgery, and palliative radiation ≤ 14 days prior to the first dose of study drug.²

About the Trial

Sevabertinib is an oral, reversible HER2 TKI. Patients were split into 3 main cohorts: patients previously treated but HER2-targeted-therapy-naive, patients previously treated with HER2-directed ADCs, and treatment-naive patients in the first-line setting.

This 4-part study examined the maximum daily dose of sevabertinib that patients can receive, tested the doses by giving the agent to more patients, determined the dose that will be tested in further studies, and determined whether the selected dose works.

Patients received sevabertinib in 3-week cycles, taking sevabertinib once or twice daily as a liquid/tablet by mouth.

Additional Studies of Sevabertinib

An expanded access program (NCT06761976)³ was conducted to provide access to sevabertinib for patients previously treated with locally advanced or metastatic NSCLC with the HER2 mutation.

The phase 2 panSOHO study (NCT06760819)⁴ is examining how the drug works in patients with different types of solid tumors with HER2 mutations.

REFERENCES

1. Siegel F, Siegel S, Kotýnková K, et al. Sevabertinib, a reversible HER2 inhibitor with activity in lung cancer. Cancer Discov (2025). doi.org/10.1158/2159-8290.CD-25-0605

2. First in human study of BAY2927088 in participants who have advanced non-small cell lung cancer (NSCLC) with mutations in the genes of epidermal growth factor receptor (EGFR) and/or human epidermal growth factor receptor 2 (HER2). ClinicalTrials.gov. Updated October 14, 2025. Accessed November 3, 2025. https://clinicaltrials.gov/study/NCT05099172

3. Expanded access to provide sevabertinib (BAY 2927088) for the treatment of locally advanced or metastatic NSCLC with HER2 mutation. ClincalTrials.gov. Updated October 23, 2025. Accessed November 4, 2025. https://clinicaltrials.gov/study/NCT06761976

4.A study to learn more about how well treatment with sevabertinib (BAY 2927088) tablets works and how safe it is in participants who have a solid tumor with mutations of the human epidermal growth factor receptor 2 (HER2) (panSOHO). ClinicalTrials.gov. Updated November 4, 2025. Accessed November 4, 2025. https://clinicaltrials.gov/study/NCT06760819