New advances in the treatment of EGFR exon20ins mutant advanced NSCLC

Abstract

The epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations, albeit less frequent, are a clinically significant subset within the EGFR mutation landscape of non-small cell lung cancer (NSCLC), accounting for roughly 4%-12% of all EGFR-altered cases. Ranking as the third most prevalent EGFR mutation type, these ex20ins mutations trail the widely recognized EGFR exon 19 deletion (19-Del) and exon 21 L858R substitution. In advanced-stage NSCLC patients with EGFR exon 20 insertion mutations, conventional treatments such as EGFR tyrosine kinase inhibitors (TKIs), chemotherapy, and immunotherapies often yield suboptimal responses, resulting in unfavorable clinical outcomes. This unmet clinical need underscores the urgency to explore innovative targeted therapies. In the realm of precision medicine, targeted agents specifically tailored for EGFR ex20ins mutations have emerged as promising candidates. This review examines the latest research on targeted therapies for EGFR ex20ins mutations, dissecting the mechanisms of action of these agents, evaluating the results of relevant clinical trials, and integrating the evidence in a systematic manner. The aim is to uncover novel therapeutic insights and strategies to optimize the clinical management of patients with EGFR ex20ins mutation-positive NSCLC.

Keywords: EGFR ex20ins; EGFR-TKIs; NSCLC; macromolecular antibodies.

Figure 1

Structure of EGFR ex20ins. EGFR ex20ins are categorized into the C-helical loop (AA 762-766), near-loop (AA 767-772), and far-loop (AA 773-775). Among these, V769_D770insASV is the most prevalent insertion variant, whereas A763_Y764 insertion is sensitive to first- and second-generation EGFR TKIs. EGFR ex20ins,epidermal growth factor receptor exon 20 insertion; TKIs, tyrosine kinase inhibitors.

Figure 2

Timeline for the discovery of targeted therapies for NSCLC patients with EGFR ex20ins mutations. EGFR, epidermal growth factor; FDA, Food and Drug Administration; NMPA, National Medical Products Administration.

Figure 3

Mechanism of action of targeted drugs, Ex20ins TKIs bind to the ATP sites of the EGFR kinase domain, inhibiting autophosphorylation and downstream pathway activation, thereby exerting anti-tumour effects. Molecular antibodies targeting EGFR and MET block ligand-induced activation, promote receptor degradation, and induce ADCP, ADCC, and CDC via immune cells, leading to tumour cell death. TKIs, tyrosine kinase inhibitors; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CDC, Complement-dependent cytotoxicity.