HER2 Overexpression Drives Drug-Tolerant Persisters to First-Line Amivantamab and Lazertinib in EGFR-Mutant Non-Small Cell Lung Cancer

In 2024, the U.S. FDA approved first-line amivantamab-lazertinib combination therapy for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) based on the MARIPOSA trial, which demonstrated superior overall survival (OS) over osimertinib. However, the underlying mechanisms of resistance to this therapy are still poorly understood. Here, we investigated the drug-tolerant state induced by amivantamab-lazertinib in a treatment-naïve NSCLC patient-derived xenograft (PDX) model with EGFR mutations. Single-cell RNA sequencing (scRNA-seq) revealed a distinct drug-tolerant persister (DTP) population characterized by increased HER2 expression. HER2 Immunohistochemistry (IHC) analysis of tumors from the PDX models demonstrated amivantamab-lazertinib therapy induced HER2 overexpression. Strikingly, biopsy samples from patients who had progressive disease (PD) following first-line amivantamab-lazertinib therapy showed increased HER2 protein expression, and in vitro studies confirmed that HER2 overexpression conferred resistance. Notably, a patient who progressed after first-line amivantamab-lazertinib with HER2 overexpression and amplification achieved a stable response with a HER2 targeted tyrosine kinase inhibitor (TKI). These findings suggest that elevated HER2 expression induced by amivantamab-lazertinib in DTPs, followed by HER2 overexpression, may serve as a resistance mechanism to first-line amivantamab-lazertinib therapy.