Prevalence and Therapeutic Targeting of High Level ERBB2 Amplification in Non-Small Cell Lung Cancer.
Academic Article
Overview
abstract
BACKGROUND: ERBB2 amplification in lung cancer remains poorly characterized. HER2 (encoded by ERBB2) is a transmembrane tyrosine kinase capable of ligand-independent dimerization and signaling when overexpressed, and a common cause of HER2 overexpression is ERBB2 amplification. Here we evaluated the clinicopathologic and genomic characteristics of ERBB2-amplified NSCLC and explored a HER2 ADC therapeutic strategy. METHODS: Our institutional next-generation DNA sequencing data (OncoPanel) from 5,769 NSCLC samples (5,075 patients) were queried for cases showing high level ERBB2 amplification (≥ 6 copies). Clinical and demographic characteristics were extracted from the electronic medical records. Efficacy of the pan-ERBB inhibitor afatinib, or HER2 ADCs [trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1)] were evaluated in NSCLC preclinical models and patients with ERBB2 amplification. RESULTS: High-level ERBB2 amplification was identified in 0.9% of lung adenocarcinomas (LUAD) and reliably predicted overexpression of HER2. ERBB2 amplification events are detected in two distinct clinicopathological and genomic subsets of NSCLC: as the sole mitogenic driver in tumors arising in patients with a smoking history, or as a concomitant alteration with other mitogenic drivers in patients with a light or never smoking history. We further show that T-DXd is effective therapy in in vitro and in vivo preclinical models of NSCLC harboring ERBB2 amplification, and report two cases of clinical activity of an anti-HER2 ADC in patients who acquired ERBB2 amplification after previous targeted therapy. CONCLUSIONS: High level ERBB2 amplification reliably predicts HER2 amplification in NSCLC patients and HER2 ADC is effective therapy in this population.
