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German National Network Genomic Medicine Suggests a Novel Classification of Atypical EGFR Mutations

Classifications is proposed according sensitivity of atypical EGFR mutations to tyrosine kinase inhibitors
11 Mar 2022

A multicentre, retrospective analysis performed by the national Network Genomic Medicine in Germany represents the largest available real-world dataset of atypical EGFR mutations. Most important findings are validation of EGFR tyrosine kinase inhibitors (TKIs) efficacy in uncommon EGFR mutations generally considered TKI-sensitive, TKI sensitivity of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner, and report of the largest clinically annotated cohort of rare single and complex EGFR point mutations revealing a high degree of heterogeneity of TKI sensitivity. Findings are published by Prof. Sonja Loges of the University Medical Centre Mannheim, University of Heidelberg and colleagues on 6 March 2022 in the Annals of Oncology.

L858R mutations and exon 19 deletions represent the most common, classical EGFR mutations in patients with non-small cell lung cancer (NSCLC) treated with EGFR TKIs in first-line setting. Retrospective studies indicate that combinations of classical EGFR mutations with other co-mutations such as TP53 can be detrimental for outcome.

The authors wrote in the background that atypical EGFR mutations comprise 10-30% of EGFR-mutated NSCLC, either alone or in combination with other EGFR mutations (atypical or classical). Only few prospective clinical studies data are available to assess the activity of EGFR TKIs in patients with atypical EGFR mutations. Sensitivity of atypical EGFR mutations to classical EGFR TKIs is highly heterogeneous. Patients harbouring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR TKI. Exon 20 insertions are mostly insensitive to EGFR TKI, but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse.

In this retrospective, multicentre study of the national Network Genomic Medicine in Germany, the researchers analyzed the frequency of atypical EGFR mutations, co-mutations and response to EGFR TKI, chemotherapy and immune checkpoint inhibitors. A total, 856 NSCLC cases with atypical EGFR mutations including co-occuring mutations were reported from 12 centres. Clinical follow-up data after treatment with different EGFR TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients.

Response to treatment was analyzed in three major groups: (1) uncommon mutations (G719X, S7681, L861Q and combinations), (2) exon 20 insertions and (3) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions).

The study comprises the largest reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. German researchers validated higher efficacy of EGFR TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR TKI responsive. In addition, they found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR TKI treated patients in groups 2 and 3, but not in group 1.

The authors commented that their data represent a large real-world dataset that will be helpful to guide treatment decisions. The EGFR TKI efficacy of uncommon EGFR mutations generally considered TKI-sensitive was validated. Complex EGFR mutations containing exon19del or L858R mutations were EGFR TKI sensitive, independent of the combination partner. Very rare single and complex mutations, comprising 40% of atypical mutations, show a high heterogeneity of TKI sensitivity. TP53 co-mutations may confer a detrimental outcome in patients treated with TKI for tumours with very rare EGFR mutations and exon20ins.

The authors also commented that the combination of in-silico and in-vitro prediction validated with clinical data will be the way forward to predict response to targeted treatments for rare mutations even beyond EGFR.

This work was funded by German Cancer Aid (Deutsche Krebshilfe), the Hector Foundation II and the Margarete Clemens Stiftung.


Janning M, Süptitz J, Albers-Leischner C, et al. Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM). Annals of Oncology; Published online 6 March 2022. DOI: https://doi.org/10.1016/j.annonc.2022.02.225.

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