The oral targeted therapy sevabertinib led to tumor reduction and manageable side effects in patients with HER2-mutant non–small cell lung cancer (NSCLC), according to data from the phase I/II SOHO-01 clinical trial. Over 70% of the patients studied saw their tumors shrink or disappear. The results were published in The New England Journal of Medicine and presented concurrently at the European Society for Medical Oncology (ESMO) Congress 2025 (Abstract LBA75) by principal investigator Xiuning Le, MD, PhD, Associate Professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.
Study Background
While platinum-based chemotherapy—and, in some cases, immunotherapy—are the standard first-line treatments for patients with advanced HER2-mutant NSCLC, opportunities remain to improve outcomes and minimize toxicity with new targeted therapies.
One such therapy, fam-trastuzumab deruxtecan-nxki, a HER2-targeted antibody-drug conjugate (ADC), has received U.S. Food and Drug Administration (FDA) accelerated approval for patients who have already been treated. However, this treatment comes with health risks, including interstitial lung disease (ILD).
The SOHO-01 trial results suggest sevabertinib, a reversible tyrosine kinase inhibitor (TKI) targeting mutant HER2 while avoiding effects on normal EGFR, may be a safe and effective option for this patient group.
“For patients with HER2-mutant lung cancer, treatment options have historically been limited and outcomes suboptimal,” Dr. Le said. “FDA approval of sevabertinib would introduce another targeted therapy option, one that precisely targets this mutation. This drug has demonstrated meaningful clinical activity with a manageable safety profile, representing a significant advance in the care of this challenging disease.”
Key Results
The open-label, multicenter SOHO-01 study enrolled 209 patients with advanced NSCLC driven by EGFR or HER2 into three different cohorts, each receiving 20 mg of sevabertinib twice a day. Cohort D included 81 patients who had received prior therapy not targeted to HER2; cohort E included 55 patients who had received HER2-targeted ADCs; and cohort F enrolled 73 patients who had not received prior therapies.
The results demonstrated sevabertinib reduced tumor activity in patients both naive to and previously treated with HER2-targeted ADCs. Diarrhea was the most common side effect, and no ILD was reported.
Of the subgroups, patients in cohort D had a response rate of 70.5%, with a median time of 8.3 months before their cancer progressed. Encouragingly, similar results were seen across different patient cohorts, no matter which treatments they had received before or whether their cancer had spread to the brain.
In May 2025, sevabertinib was granted Priority Review for accelerated approval by the FDA. This came after it received the FDA’s 2024 Breakthrough Therapy designation. The results of SOHO-01 support the New Drug Approval submitted to the FDA.
Disclosure: For full disclosures of the study authors, visit nejm.org.
