Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations

Abstract

Non-small-cell lung cancer (NSCLC) harbouring HER2 alterations is now considered a distinct molecular subtype. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% of cases), gene amplification (2%-5%) and protein overexpression (2%-30%), with different prognostic and predictive outcomes. So far, non-selective tyrosine kinase inhibitors (TKIs) have shown a minor benefit in H ER 2 -mutant NSCLC patients with objective response rates (ORRs) ranging from 0% to 19%. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone [median progression-free survival (PFS) 6.1 versus 7 months, respectively] and dual HER2 antibody blockade with trastuzumab and pertuzumab had limited efficacy (ORR 13%-21%). In contrast, novel more selective HER2 TKIs such as poziotinib and pyrotinib have shown a promising activity in H ER 2 -mutant pre-treated NSCLC patients, with response rates up to 38% and 44%, respectively. The most encouraging data come from phase II studies that evaluated the antibody–drug conjugates (ADCs) ado-trastuzumab–emtansine and trastuzumab–deruxtecan in patients with H ER 2 -mutant NSCLC, with response rates of 50% and 62%, respectively. These agents are bringing hope to the management of HER2-altered NSCLC. Moreover, a paradigm shift from monotherapies towards combinations of agents with distinct mechanisms of action, such as ADCs with irreversible TKIs or immune checkpoint inhibitors, is already taking place and will change the therapeutic landscape of HER2-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with HER2 molecular alterations.

Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma

“…Our results suggest an inner association between the MIP aggressive phenotype and neurogenesis. The activation of well-known proto-oncogene ERBB2 signaling was associated with poor outcomes in NSCLC ( 34 ), coinciding with MIP characteristics. The copy number of genes related to the immune system, innate immune system, interleukin signaling, SHC1 events, ERK activation, and FRS-mediated signaling were also found to decrease in MIP.…”

Multi-Omics Integration-Based Prioritisation of Competing Endogenous RNA Regulation Networks in Small Cell Lung Cancer: Molecular Characteristics and Drug Candidates

“…Interestingly, the DrugBank analysis showed that the drug targeting GAA was Trastuzumab-deruxtecan. Trastuzumab-deruxtecan is primarily used for patients with human epidermal growth factor receptor 2 (HER2)-mutant tumours including non-SCLC and in the absence of SCLC (79)(80)(81). Upon binding to HER2, Trastuzumab-deruxtecan disrupts the HER2 signalling, undergoes internalisation and intracellular linker cleavage by lysosomal enzymes and ultimately causes DNA damage and apoptotic cell death (80).…”

Challenges of Systemic Therapy Investigations for Bone Sarcomas

“…Human epidermal growth factor receptor 2 (HER2) is well known as the target in many cancer treatments. HER2-targeted therapy is established as the standard treatment for breast cancer and gastric adenocarcinoma [ 46 , 47 ], and it is recently being investigated for other solid tumors such as non-small cell lung cancer and colorectal cancer [ 48 , 49 ]. Overexpression of HER2 is observed in approximately 30% of osteosarcoma cases and was suggested to be poor-prognosis factor [ 50 , 51 ], and thus HER2 could be a candidate for the targeted therapy of osteosarcoma.…”