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

Giulio Metro, Andrea De Giglio, Biagio Ricciuti, Marco Siringo, Daniele Marinelli, Alain Gelibter, Federica Pecci, Rossana Berardi, Luca Cantini, Alessandro Di Federico, Elisa Andrini, Mirta Mosca, Giuseppe Lamberti, Marta Brambilla, Giannis Mountzios


EGFR exon 20 insertion mutations (Ex20ins) and HER2 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 HER2-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.

This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue:

Article Details

Article Type




Publication Dates

Accepted: ; Published: .


Metro G, De Giglio A, Ricciuti B, Siringo M, Marinelli D, Gelibter A, Pecci F, Berardi R, Cantini L, Di Federico A, Andrini E, Mosca M, Lamberti G, Brambilla M, Mountzios G. Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease. Drugs Context. 2022;11:2022-3-9.

Register for alerts

I would like to be contacted by Drugs in Context when new articles are posted.