HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies

Abstract

Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung cancer (NSCLC) in recent years. Activating HER2 alterations in NSCLC include gene mutations, gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now a well clinically validated biomarker. Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations are present in 7–27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of EGFR mutated NSCLC. There has been an influx of research on antibody–drug conjugates (ADCs), monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib, mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration to better select patients who will benefit, particularly for HER2 amplification and overexpression. Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of patients with HER2 altered NSCLC.

Profiling of ERBB receptors and downstream pathways reveals selectivity and hidden properties of ERBB4 antagonists

“…Next, we sought to challenge the barcoded ERBBprofiler assay and selected various ERBB receptor antagonists, which included approved drugs (erlotinib, gefitinib, lapatinib, osimertinib), 22 , 24 , 41 , 42 but also a failed compound (AG1478), 43 and drug candidates that are in a clinical trial stage (poziotinib, pyrotinib, TAS6417). 44 , 45 , 46 Clozapine was selected as an approved drug for targeting HTR2A. 47 As antagonist assays require activated receptors and pathways, we selected the mix of ligands to stimulate ERBB receptors and HTR2A, as well as signaling pathways.…”

Cutting-Edge Therapies for Lung Cancer

“…Furthermore, pan-HER TKIs like afatinib, neratinib, and dacomitinib have been used to treat patients with HER2-mutant NSCLC [ 71 ]. Selective HER2 tyrosine kinase inhibitors (TKIs) such as pyrotinib, poziotinib, mobocertinib, tarloxotinib, afatinib, neratinib, and dacomitinib have been employed in lung cancer treatment [ 72 ]. For instance, clinical studies have indicated that pyrotinib can enhance the overall survival of NSCLC patients with HER2 mutations, regardless of metastatic status [ 73 ].…”

Advances in Genomic Data and Biomarkers: Revolutionizing NSCLC Diagnosis and Treatment

“…Mutation in FGFR1 contributes to the promotion of mesenchymal-predominant NSCLC [ 60 ]. Additionally, Discoidin domain Receptor 2 (DDR2), a tyrosine kinase, is considered as a biomarker, as its mutation promotes tumor growth, particularly in 30% of squamous NSCLC [ 61 ]. Furthermore, the human epidermal growth factor receptor 2 (HER2), involved in activating cell proliferation pathways such as PI3K-AKT and MEK-ERK, is found in 10 to 30% of NSCLC cases, especially in adenocarcinoma [ 62 ].…”