A comprehensive overview of the heterogeneity of EGFR exon 20 variants in NSCLC and (pre)clinical activity to currently available treatments

• Published in: Cancer treatment reviews 2023-11, Vol.120, p.102628-102628, Article 102628
• Main Authors: Zwierenga, Fenneke, van Veggel, Bianca A.M.H., van den Berg, Anke, Groen, Harry J.M., Zhang, Lili, Groves, Matthew R., Kok, K., Smit, E.F., Hiltermann, T. Jeroen N., de Langen, Adrianus J., van der Wekken, Anthonie J.
• Format: Article
• Language: English
• Subjects: EGFR; Exon 20 mutation; NSCLC; TKIs
• ISSN: 0305-7372; 1532-1967
• DOI: 10.1016/j.ctrv.2023.102628

•EGFRex20+ NSCLC patients are treated irrespective of the location of the mutation;•The EGFRex20+ mutation location is the main determinant for selecting the optimal therapy;•The A763_Y764insFQEA mutation should be treated different;•A structural understanding of the impact of EGFRex20+ mutations is warranted. Activating EGFR mutations are commonly observed in non-small cell lung cancer (NSCLC). About 4–10 % of all activating epidermal growth factor receptor (EGFR) mutations are heterogenous in-frame deletion and/or insertion mutations clustering within exon 20 (EGFRex20+). NSCLC patients with EGFRex20+ mutations are treated as a single disease entity, irrespective of the type and location of the mutation. Here, we provide a comprehensive assessment of the literature reporting both in vitro and clinical drug sensitivity across different EGFRex20+ mutations. The activating A763_Y764insFQEA mutation has a better tumor response in comparison with mutations in the near- and far regions directly following the C-helix and should therefore be treated differently. For other EGFRex20+ mutations marked differences in treatment responses have been reported indicating the need for a classification beyond the exon-based classification. A further classification can be achieved using a structure–function modeling approach and experimental data using patient-derived cell lines. The detailed overview of TKI responses for each EGFRex20+ mutation can assist treating physicians to select the most optimal drug for individual NSCLC patients.