Abstract A036: A subset of lung adenocarcinomas defined by high-level ERBB2 amplification is vulnerable to HER2-targeted therapy
Authors: Odintsov Igor , Makarem Maisam , Bachert Sara E. , Zhang Tom , Somwar Romel , Jänne Pasi A. , Sholl Lynette M. 
Published: December 2023

Abstract
Background: Most lung adenocarcinomas (LUAD) are driven by activation of receptor tyrosine kinases (RTK). HER2 (encoded by ERBB2) is an RTK capable of ligand-independent dimerization and signaling when overexpressed. ERBB2 amplification (ERBB2amp) is a common cause of HER2 overexpression. While activating ERBB2 mutations (e.g., ERBB2 exon 20 YVMA insertions) are targetable drivers of LUAD, the role of ERBB2amp in lung cancer (LC) is unclear and there is no FDA-approved therapy for this indication in LC. Here, we report the clinicopathological and molecular characteristics of LUAD with high-level ERBB2amp and investigate the efficacy of HER2-targeted agents in LC models with ERBB2amp. We also demonstrate the clinical benefit of trastuzumab-deruxtecan (T-DXd) in a patient with ERBB2amp LUAD.
Design: An institutional database of hybrid capture DNA NGS panel targeting 290-447 genes (v1-v3.1) was interrogated for LUAD with high-level ERBB2amp (defined as at least 6 calculated gene copies by NGS). HER2 immunohistochemistry (IHC) was performed on 29 available cases and scored according to ASCO/CAP scoring criteria. HER2 IHC scores of 2+ and 3+ were considered overexpression. Two LC cell lines, H2170 and CALU3 were identified as ERBB2amp and their responses to HER2 inhibitors were characterized with Western blotting, viability, and apoptosis assays. CALU3 and H2170 xenograft models were also established and treated with HER2 inhibitors or T-DXd.
Results: ERBB2amp was identified in 31/3,684 (0.8%) LUAD patients. HER2 overexpression was present in 24 out of 29 evaluable cases (79.3%). Eighteen cases (58%) showed high-level ERBB2amp with no concurrent drivers and were more likely to be male (P = 0.001) and have a history of tobacco use (P = 0.001), compared to patients with high-level ERBB2amp with a concurrent driver mutation (activating ERBB2 SNV/indels, activating EGFR and MET mutations, RET fusion). H2170 and CALU3 cells displayed overexpression of HER2 and phospho-HER2, and growth of these cells showed sub-nanomolar sensitivity to trastuzumab and T-DXd, and low nanomolar sensitivity to afatinib. T-DXd induced apoptosis in both cell lines (assessed by activation of caspase 3/7 and elevation of BIM and cleaved PARP levels). While trastuzumab and afatinib significantly slowed down growth of H2170 and CALU3 xenografts, only T-DXd achieved tumor shrinkage equivalent to partial (H2170) or complete response (CALU3) in all animals. We describe the case of a LUAD patient with a RET rearrangement who acquired high-level ERBB2amp after progression on selpercatinib and was treated with T-DXd, with evidence of disease stability and clinical benefit.
Conclusion: High-level ERBB2 amplification detected by NGS reliably predicts HER2 overexpression in lung adenocarcinoma. LUAD with ERBB2 amplification and no concurrent oncogenic drivers is a rare event that occurs predominantly in male smokers. This data can inform future trials investigating the utility of HER2-targeting agents in this population.
Citation Format: Igor Odintsov, Maisam Makarem, Sara E. Bachert, Tom Zhang, Romel Somwar, Pasi A. Jänne, Lynette M. Sholl. A subset of lung adenocarcinomas defined by high-level ERBB2 amplification is vulnerable to HER2-targeted therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A036.