Sevabertinib Demonstrates Robust Antitumor Activity in HER2-Mutated Non-Small Cell Lung Cancer
Key Clinical Takeaways
- Design/Population: This open-label, multicenter phase 1/2 study evaluated sevabertinib 20 mg twice daily in 209 patients with locally advanced or metastatic HER2-mutant NSCLC. Patients were enrolled into 3 cohorts based on prior HER2-targeted therapy exposure: previously treated (no HER2 therapy), prior HER2-directed antibody–drug conjugates, and treatment-naive.
- Key Outcomes: Objective responses were observed across all cohorts, including ORRs of 64% in previously treated patients, 38% in prior ADC-treated patients, and 71% in treatment-naive patients. Median duration of response ranged from 8.5 to 11.0 months, and progression-free survival was most mature in cohorts D and E at 8.3 months and 5.5 months, respectively.
- Clinical Relevance: Sevabertinib demonstrated clinically meaningful antitumor activity in HER2-mutant NSCLC across multiple lines of therapy. Diarrhea was the most common adverse event, but discontinuation rates were low, supporting sevabertinib as a promising emerging targeted therapy in this molecular subset.
Results from the phase 1/2 SOHO-01 trial demonstrate that sevabertinib, an anti-HER2 tyrosine kinase inhibitor, shows promising antitumor activity among patients with locally advanced or metastatic HER2-mutated non–small cell lung cancer (NSCLC).
In this open-label study, researchers enrolled 209 patients and stratified them into 3 cohorts based on prior treatment history: those previously treated without HER2-targeted therapy (cohort D; n = 81), those previously treated with HER2-directed antibody-drug conjugates (cohort E; n = 55), and treatment-naive patients (cohort F; n = 73). Patients received 20 mg of sevabertinib twice daily.
The primary end point was objective response rate (ORR), assessed by blinded independent central review. Key secondary end points included duration of response, progression-free survival (PFS), and safety.
At analysis, cohort D demonstrated an ORR of 64%, with a median duration of response of 9.2 months and a median PFS of 8.3 months. In cohort E, the ORR was 38%, with a median duration of response of 8.5 months and a median PFS of 5.5 months. In cohort F, the ORR was 71%, with a median duration of response of 11 months; PFS data for this cohort were immature at the time of analysis.
Grade ≥3 treatment-related adverse events occurred in 31% of patients and most commonly included diarrhea (5% to 23%). Treatment-related adverse events led to treatment discontinuation in 3% of patients.
Source:
Le X, Kim TM, Loong HH, et al. Sevabertinib in advanced HER2-mutant non–small-cell lung cancer. N Engl J Med. Published online: October 17, 2025. doi:10.1056/NEJMoa2511065
