Dr Le on the Mechanism of Action of Sevabertinib in HER2-Mutated NSCLC

“Sevabertinib is an oral, [reversible] small molecule inhibitor of HER2 that is very potent against HER2 insertions and kinase mutations.”

Xiuning Le, MD, PhD, associate professor in the Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center, broke down the mechanism of action of sevabertinib (Hyrnuo) in patients with advanced HER2-mutated non–small cell lung cancer (NSCLC).

Sevabertinib is an oral, reversible HER2-directed TKI that has shown potent efficacy against HER2 insertions and kinase mutations, Le began. The agent is being evaluated in the phase 1/2 SOHO-01 trial (NCT05099172) as monotherapy in patients with HER2-mutant advanced NSCLC. Le added that the preclinical data preceding the study were strong.

At a median follow-up of 13.8 months (range, 1-32), findings from SOHO-01 presented by Le during the 2025 ESMO Congress demonstrated that previously treated patients who were naive to HER2-targeted therapies and received sevabertinib (n = 81) achieved an overall response rate of 64% (95% CI, 53%-75%) per RECIST 1.1 criteria by blinded independent central review, including a complete response rate of 2%. The median duration of response and progression-free survival values were 9.2 months (95% CI, 6.3-13.5) and 8.3 months (95% CI, 6.9-12.3), respectively.

In November 2025, the FDA granted accelerated approval to sevabertinib for the treatment of adult patients with locally advanced or metastatic, nonsquamous NSCLC with tumors harboring HER2 TKD activating mutations, as detected by an FDA-approved test, who have previously received 1 line of systemic therapy. The regulatory decision was supported by data from SOHO-01.

Disclosures: Le holds consulting roles or received advisory fees from AbbVie, Abion, Akeso, Allist, ArriVent, AstraZeneca, Avistone, Bayer, BioNTech, BlossomHill, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Dizal, Eli Lilly, EMD Serono (Merck KGaA), Hengrui, Innovent, Johnson & Johnson (Janssen), Merck, Novartis, Pfizer, Regeneron, Summit, SystImmune, Taiho, and. Teligene She also received institutional research funding from ArriVent, Dizal, Eli Lilly, EMD Serono, Johnson & Johnson (Janssen), Regeneron, Takeda, Teligene, and Thermo Fisher.