Molecular Landscape of Acquired Resistance to Sevabertinib in HER2-mutant NSCLC: Exploratory Biomarker Analysis of SOHO-01

Xiuning Le, MD, PhD

MD Anderson Cancer Center

Dr. Le is presenting her work at the World Conference on Lung Cancer in Seoul, South Korea on Sept. 15, 2026. Session info

Dr. Le received the 2025 LCRF | Bayer Research Award on Innovative Therapeutic Strategies to Treat Lung Cancers Harboring HER2 Mutations and/or Other HER2 Alterations for her project, Characterization of HER2 Mutations’ Sensitivity to Sevabertinib & Development of Novel Combination Strategies to Overcome Resistance to Current HER2 Therapies.

HER2 mutations are found in approximately 2–4% of non-small cell lung cancers (NSCLC) and are associated with poor outcomes. Sevabertinib is a targeted therapy designed specifically to inhibit HER2 and has shown promising results in patients with advanced HER2-mutant NSCLC, including both newly diagnosed and previously treated patients.

One important question is why some cancers eventually begin growing again despite treatment. This study analyzed blood samples from patients participating in the Phase 1/2 SOHO-01 clinical trial to identify genetic changes that may help explain how HER2-mutant lung cancers develop resistance to sevabertinib.

Exciting findings so far

  • Researchers were able to compare blood samples collected before treatment and around the time of disease progression for 73 patients whose tumors had detectable HER2 mutations at the start of treatment. The molecular landscape of most patients’ cancers remained relatively stable; however, researchers identified potential genetic mechanisms of resistance in 22 of them.
  • The most common potential resistance mechanism was a secondary change in HER2 called T862A, which emerged in 12 of 73 patients, suggesting that T862A may be an important mechanism by which some HER2-mutant cancers develop resistance to sevabertinib.
  • Importantly, most patients whose disease progressed did not have an identifiable genetic resistance mechanism. This suggests that other processes, including nongenetic or adaptive changes in cancer cells, may also contribute to resistance. C805S mutations were not detected.

What’s next

  • Researchers are conducting studies in the laboratory and structural modeling to better understand how the HER2 T852A alteration affects sevabertinib’s ability to inhibit HER2.
  • Because most patients did not have an identifiable genetic cause of resistance to the drug, additional research is needed to understand other ways that HER2-mutant lung cancer cells adapt to escape treatment.

Important to know

  • The HER2 T862A alteration emerged as the most common potential genetic mechanism of resistance identified in this analysis. However, patients who developed T862A had a similar duration of response and time to disease progression as patients who did not develop the alteration.
  • The findings presented here are from an exploratory biomarker analysis of the SOHO-01 clinical trial. More studies are underway to determine the significance of the T862A alteration and how it affects the ability of sevabertinib to inhibit HER2.