Previously Funded Research

Sarah Goldberg, MD, MPH

Yale School of Medicine

Research Project:

Stratifying and Personalizing for HER2 Mutated Lung Cancers

Summary:

Up to 4% of non-small cell lung cancers (NSCLC) have a mutation in the HER2 gene that drives the cells to grow and divide inappropriately. Progress in developing therapies for HER2-mutant lung cancer has lagged behind other oncogene-driven lung cancers but several recent studies have demonstrated that HER2-directed therapies that can positively impact patients.

Trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate that targets HER2 on the cell surface and then delivers a chemotherapeutic payload directly to the tumor cell, selectively killing it as a result. T-DXd was demonstrated to have clinical activity in patients with advanced HER2-mutant lung cancer after prior therapy, representing the first (and only) treatment approved by the FDA specifically for patients with HER2-mutant lung cancer. There are also several HER2-directed tyrosine kinase inhibitors (TKIs) that are currently in development and have promising results.

TKIs are small molecules that directly block the ability of HER2 to promote uncontrolled cell growth, but they are more effective against HER2 with certain mutations that with others – in ways that are not yet understood. Despite these clear advances in treating HER2-mutant lung cancer, there are still many unanswered questions that hinder further progress and which we intend to answer with this proposal.

We are a highly collaborative team of clinical, translational and basic science groups, led by a clinical scientist who is running clinical trials in HER2-mutant lung cancer. We work together closely to ensure that our clinical trials are driven by a precise understanding of how the different therapeutic agents work, directly linking understanding of molecular structure and biochemistry to clinical application. Here we address the problem that HER2 mutations to date have all typically been grouped together as one entity, so that all patients are treated in the same way. However, we have demonstrated that lung cancer can have many different types of HER2 mutations that occur in different parts of the gene, and have very different effects on HER2 as a signaling molecule – and this can significantly impact response to treatment.

Our goal is to use our combined expertise to understand the molecular effects of each mutation and then to tailor treatment choice based on these considerations. We test our ideas in laboratory studies. Once we understand how to select the appropriate treatment based on patients’ mutations, we test those choices in clinical trials. In this study, we will first address whether (and how) the specific HER2 mutation and its location within the gene impacts the activity of the various HER2-directed drugs, including T-DXd and different HER2 TKIs. Second, we will explore the causes of resistance to different HER2 therapies, with the purpose of learning how to best overcome drug resistance.

The ultimate goal from this research is to personalize upfront therapy for patients with HER2-mutant lung cancer based on a molecular understanding of the specific mutation present and to develop informed strategies to overcome treatment resistance.