Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease

Abstract

EGFR exon 20 insertion mutations (Ex20ins) and HER 2 mutations characterize an oncogene-addicted subtype of non-small-cell lung cancer (NSCLC) typically associated with a never or light smoking history, female sex, and adenocarcinoma histology. Nevertheless, Ex20ins-mutant and HER 2-mutant advanced NSCLCs are still difficult to treat for various reasons. First, there is a need for sophisticated diagnostic tools (e.g. next-generation sequencing) that could allow the identification of these relatively rare molecular drivers. Second, highly active targeted drugs that might support a significant change in patients’ prognosis when used as first-line therapy are required. In fact, although a few targeted drugs have so far demonstrated antitumour activity for these patients, mainly selective human epidermal receptor-tyrosine kinase inhibitors such as poziotinib and mobocertinib (for both molecular alterations), monoclonal antibodies such as amivantamab (for Ex20ins), and antibody–drug conjugates such as trastuzumab deruxtecan (for HER2 mutants), they are mostly confined for clinical use in pretreated patients. Finally, Ex20ins-targeted or HER2-targeted drugs might be difficult to access in different countries or regions worldwide. In the present review, we provide a concise but comprehensive summary of the challenges that lie ahead as we move towards personalized treatment of Ex20ins-mutant and HER2 -mutant advanced NSCLC, also suggesting a treatment algorithm that could be followed for patients with these genetic aberrations.

Overexpression of TWF1 promotes lung adenocarcinoma progression and is associated with poor prognosis in cancer patients through the MMP1 signaling pathway

“…Lung cancer is the leading cause of cancer-related death globally, and LUAD is the most common subtype ( 13 ). The popularization of spiral chest computed tomography (CT) has facilitated the diagnosis of patients with early-stage lung cancer ( 5 , 14 ).…”

“…The promotion of non-surgical treatment such as targeted therapy has saved many patients with mid-/late-stage cancers. Epidermal growth factor receptor (EGFR) mutation is one of the driver mutations for LUAD ( 13 , 15 ). Multiple EGFR-targeted tyrosine kinase inhibitors (TKIs; e.g., gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) have been determined as standard initial treatment for patients harboring EGFR mutations, which has saved numerous patients with mid-/late-stage cancers ( 15 , 16 ).…”

The expanding scenario of advanced non-small-cell lung cancer between emerging evidence and clinical tasks

“…Finally, several phase II trials are promisingly expanding the therapeutic scenario of rare driver alterations amenable to targeted therapy and, recently, the approbation of agnostic drugs reverted the hierarchy between histology and molecular targets. 3 , 5 – 8 …”