FDA Approves Sevabertinib for Advanced HER2 TKD–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 harbor HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-authorized test.¹

This approval was supported by data from the open-label, single-arm, multicenter, multicohort phase 1/2 SOHO-01 trial (NCT05099172) of sevabertinib in patients with locally advanced or metastatic nonsquamous NSCLC with HER2 (ERBB2) TKD activating mutations, which were identified in tumor tissue or plasma by local laboratories before enrollment. Among evaluable patients who had not received prior systemic therapy (n = 69), the overall response rate (ORR) was 75% (95% CI, 64%-85%). Additionally, 73% of responders achieved a duration of response (DOR) of at least 6 months, and 38% had a DOR lasting at least 12 months.

This regulatory decision expands the existing indication for sevabertinib, which was granted accelerated approval in November 2025 for the treatment of adult patients with locally advanced or metastatic nonsquamous NSCLC harboring HER2 (ERBB2) TKD activating mutations who have received prior systemic therapy.

What was the design of the SOHO-01 trial?

SOHO-01 was designed to investigate the efficacy and safety of the oral, reversible, small-molecule tyrosine kinase inhibitor sevabertinib in patients with unresectable or metastatic nonsquamous NSCLC harboring HER2 (ERBB2) TKD activating mutations. ORR served as a primary efficacy end point.² Secondary end points included DOR, progression-free survival (PFS), and safety.

Cohort F enrolled patients who had not previously received systemic anticancer therapy for locally advanced or metastatic disease.

Enrollment occurred between October 25, 2021, and December 24, 2024. HER2 TKD mutations were present in 97% of patients in cohort F, and 4% of patients in this cohort had received prior platinum-based chemotherapy and immunotherapy.

Patients were treated with sevabertinib at a dose of 20 mg twice daily.

What additional efficacy data from SOHO-01 are important to note?

In data published in the New England Journal of Medicine in October 2025, among evaluable treatment-naive patients (n = 73), at a data cutoff of June 27, 2025, the confirmed ORR was 71% (95% CI, 59%-81%), the median PFS was not evaluable (NE; 95% CI, 9.6 months-NE), and the median DOR was 11.0 months (95% CI, 8.1-NE).

Among patients with baseline brain metastases in cohort F (n = 9), responses occurred in 78%. At a median follow-up of 9.9 months (range, < 1-15) in cohort F, 66% of patients were still receiving treatment.

What was the safety profile of sevabertinib in cohort F of SOHO-01?

The most common adverse effects (AEs) that were deemed related to study treatment with sevabertinib were diarrhea (84%), rash (51%), paronychia (22%), stomatitis (26%), and anemia (22%). AEs were mainly grade 1 (19%) or grade 2 (55%), although grade 3 (21%), 4 (1%), and 5 (1%) AEs were also reported.

Diarrhea was reported at grade 3 in 5% of patients and led to dose reductions in 7% of patients in cohort F, although there were no reports of grade 4 diarrhea or treatment discontinuations due to diarrhea. Sevabertinib-related AEs led to dose reductions and treatment discontinuation in 25% and 1% of patients, respectively, in this cohort. Serious drug-related AEs were seen in 8% of patients in cohort F. No cases of interstitial lung disease or pneumonitis were reported.

References

1. FDA grants accelerated approval to sevabertinib for locally advanced or metastatic non-squamous non-small cell lung cancer. 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. Le X, Kim TM, Loong HH, et al. Sevabertinib in advanced HER2-mutant non-small-cell lung cancer. N Engl J Med. 2025;393(18):1819-1832. doi:10.1056/NEJMoa2511065