FDA Grants Accelerated Approval to Sevabertinib in HER2-Mutated Nonsquamous NSCLC

The FDA has granted accelerated approval to sevabertinib (Hyrnuo) for the treatment of adult patients with locally advanced or metastatic, nonsquamous non–small cell lung cancer (NSCLC) whose tumors have HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.1

The approval is supported by efficacy and safety findings from the phase 1/2 SOHO-01 trial (NCT05099172), which evaluated sevabertinib in patients with HER2-mutated advanced NSCLC across multiple treatment cohorts.1,2

Findings suppoting the approval showed that patients with locally advanced or metastatic NSCLC harboring HER2 TKD activating mutations who had received prior systemic therapy and were naive to HER2-targeted therapy (n = 70) achieved an overall response rate (ORR) of 71% (95% CI, 59%-82%) and a median duration of response (DOR) of 9.2 months (95% CI, 6.3-15.0).1 The 6-month DOR rate in this population was 54%.

Furthermore, patients with locally advanced or metastatic NSCLC harboring HER2 TKD activating mutations who had received prior systemic therapy, including HER2-targeted antibody-drug conjugates (n = 52), experienced an ORR of 38% (95% CI, 25%-53%) and a median DOR of 7.0 months (95% CI, 5.6-not evaluable). The 6-month DOR rate was 60% in this group.

What data were previously reported from SOHO-01?

Earlier results from SOHO-01 were presented at the IASLC 2024 World Conference on Lung Cancer. In that analysis, evaluable patients who received sevabertinib at the 20-mg twice-daily dose (n = 43) experienced an ORR of 72.1% (95% CI, 56.3%–84.7%), which included a 2.3% complete response rate. The median DOR in the overall cohort was 8.7 months (95% CI, 4.5–not estimable), and the median progression-free survival (PFS) was 8.7 months (95% CI, 4.4–12.2). Notably, patients with HER2 YVMA mutations experienced particularly robust activity, achieving an ORR of 90.0%, a median DOR of 9.7 months, and a median PFS of 9.9 months, underscoring the relevance of mutation subtype in treatment sensitivity.

What was the design of the SOHO-01 trial?

Sevabertinib is an oral, small molecule HER2-selective tyrosine kinase inhibitor that previously received FDA breakthrough therapy designation for adult patients with unresectable or metastatic HER2-mutated NSCLC following prior systemic therapy. SOHO-01 was a first-in-human, open-label, multicohort study enrolling adults with recurrent or metastatic NSCLC that had progressed after at least one prior systemic regimen. Patients were required to have documented EGFR and/or HER2 mutations, measurable disease by RECIST 1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and adequate bone marrow and organ function.

Key exclusions included any history of primary brain or leptomeningeal disease, symptomatic central nervous system (CNS) metastases, CNS metastases requiring local therapy, and a history of congestive heart failure.

The study included dose-escalation, backfill, dose-expansion, and dose-extension phases. The escalation phase characterized safety and established dose-limiting toxicities. The backfill and expansion phases further evaluated doses deemed tolerable to identify the recommended phase 2 dose, while the extension phase confirmed efficacy at the selected dose.

Primary end points included safety, dose-limiting toxicities, maximum tolerated dose determination, pharmacokinetic characterization, and blinded independent central review–assessed ORR. Secondary end points included investigator-assessed ORR, DOR, disease control rate, PFS, and overall survival.

In safety-evaluable patients (n = 44), 95.5% experienced treatment-related adverse effects (TRAEs). Grade 3 TRAEs occurred in 40.9% of patients. The most common TRAEs included diarrhea (86.4%), rash (43.2%), and paronychia (25.0%). Treatment discontinuation due to AEs occurred in 6.8% of patients.

Sevabertinib is being further evaluated in the global, randomized phase 3 SOHO-02 trial (NCT06452277), which is comparing sevabertinib with standard-of-care systemic therapy in patients with previously untreated advanced HER2-mutated NSCLC. Results from SOHO-02 are expected to clarify the agent’s role in the first-line setting and inform sequencing strategies across the continuum of care.

References

1. FDA grants accelerated approval to sevabertinib for non-squamous non-small cell lung cancer. FDA. November 19, 2025. Accessed November 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sevabertinib-non-squamous-non-small-cell-lung-cancer
2. New results from the Investigational agent BAY 2927088 in HER2-mutant non-small cell lung cancer (NSCLC) presented at WCLC. News release. Bayer. September 9, 2024. Accessed May 28, 2025. https://www.bayer.com/media/en-us/new-results-from-the-investigational-agent-bay-2927088-in-her2-mutant-non-small-cell-lung-cancer-nsclc-presented-at-wclc/
3. 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 May 13, 2025. Accessed November 5, 2025. https://clinicaltrials.gov/study/NCT05099172
4. A study to learn more about how well BAY 2927088 works and how safe it is compared with standard treatment, in participants who have advanced non-small cell lung cancer (NSCLC) with mutations in the genes of human epidermal growth factor receptor 2 (HER2) (SOHO-02). ClinicalTrials.gov. Updated April 8, 2025. Accessed May 28, 2025. https://clinicaltrials.gov/study/NCT06452277