Exploring the Potential Role of HER3-DXd in Advanced EGFRm Non–Small Cell Lung Cancer

This video segment explores the emerging role of HER3-targeted antibody-drug conjugates (ADCs), specifically patritumab deruxtecan (HER3-DXd), in treating advanced EGFR-mutated non–small cell lung cancer. The discussion highlights how this new class of therapeutics could significantly change the treatment landscape for later-line therapy in this patient population. HER3 represents an intriguing target because it’s not typically mutated or amplified at resistance but is overexpressed in EGFR-mutated lung cancer, making it an attractive therapeutic avenue.

Clinical data from single-arm phase 2 studies demonstrate promising activity for patritumab deruxtecan in the postchemotherapy, post–tyrosine kinase inhibitor (TKI) setting, with response rates around 30% and median progression-free survival of approximately 6 months. Notably, the agent shows encouraging intracranial activity, which is particularly valuable given the limited central nervous system (CNS)-active options beyond TKI-based therapies and pemetrexed. The drug appears effective across various resistance mechanisms, including C797S resistance mutations, suggesting broad applicability. Importantly, preliminary data from randomized studies comparing patritumab deruxtecan to chemotherapy show improved outcomes, potentially positioning this agent for second-line use, especially following frontline combination regimens.

A particularly intriguing aspect of HER3-DXd is that its activity doesn’t correlate with HER3 protein expression levels, meaning there’s currently no biomarker for patient selection and treatment decisions remain empirical. The mechanism of CNS penetration for ADCs remains unclear, with speculation about whether it’s due to the antibody component, the cytotoxic payload distribution, or blood-brain barrier disruption in the presence of metastases. This lack of predictive biomarkers presents both opportunities and challenges, as the drug may benefit patients across different molecular profiles but requires empirical treatment approaches rather than precision-guided selection.