Previously Funded Research

Xiuning Le, MD, PhD

University of Texas MD Anderson Cancer Center

Research Project:

Characterization of HER2 Mutations’ Sensitivity to Sevabertinib & Development of Novel Combination Strategies to Overcome Resistance to Current HER2 Therapies

Summary:

Advances in targeted therapy have significantly improved outcomes for lung cancer patients with specific mutations. One such group includes patients with mutations in the HER2 gene (also known as ERBB2), which is found in about 3% of non-small cell lung cancer (NSCLC) cases—more than 10,000 people in the U.S. each year. These mutations occur in different regions of the HER2 protein and are usually not found with other common cancer-driving mutations, making them a unique and targetable subgroup. Currently, the only FDA-approved HER2-targeted therapy for lung cancer is trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate. While T-DXd has shown good results, nearly half of patients do not respond and eventually develop resistance. No small molecule drugs (called tyrosine kinase inhibitors or TKIs) have yet been approved for HER2-mutant lung cancer.

A promising new oral medicine, sevabertinib, is showing strong results in clinical trials. It is an oral TKI that specifically targets HER2. In early studies, it has led to tumor shrinkage in over 70% of patients and earned FDA Breakthrough Therapy Designation. Sevabertinib is now being evaluated as a first-line treatment in a large international trial.

However, there are still unanswered questions. First, HER2 mutations can happen in different locations of the HER2 gene, and we don’t yet know which ones respond best to sevabertinib—or which may resist it. Second, cancers that become resistant to HER2 treatments may still be vulnerable to other strategies, such as combining sevabertinib with antibodies or drugs that target related proteins on the cancer cell surface.

To address these challenges, our research will:

• Map how different HER2 mutations respond to sevabertinib, using both lab-grown cells and patient data from clinical trials. We will identify which mutations predict drug response and which cause resistance, including those that arise during treatment.
• Find new ways to overcome drug resistance, especially in patients whose cancer no longer responds to T-DXd or sevabertinib. We will test combination treatments that target HER2 and other proteins to boost and prolong the benefit of therapy.
• By understanding who benefits from sevabertinib and how resistance develops, this research will pave the way for personalized treatment strategies—ensuring patients get the most effective therapies and new options when current treatments stop working.