Abstract
Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC). Classical activating mutations (exon 19 deletions and the L858R point mutation) comprise the vast majority of EGFR mutations and are well defined as strong predictors for good clinical response to EGFR tyrosine kinase inhibitors (EGFRi). However, low frequency mutations including point mutations, deletions, insertions and duplications occur within exons 18–25 of the EGFR gene in NSCLC and are associated with poorer responses to EGFRi. Despite an increased uptake of more sensitive detection methods to identify rare EGFR mutations in patients, our understanding of the biology of these rare EGFR mutations is poor compared to classical mutations. In particular, clinical data focused on these mutations is lacking due to their rarity and challenges in trial recruitment, resulting in an absence of effective treatment strategies for many low frequency EGFR mutations. In this review, we describe the structural and mechanistic features of rare EGFR mutations in NSCLC and discuss the preclinical and clinical evidence for EGFRi response for individual rare EGFR mutations. We also discuss EGFRi sensitivity for complex EGFR mutations, and conclude by offering a perspective on the outstanding questions and future steps required to make advances in the treatment of NSCLC patients that harbour rare EGFR mutations.
Highlights
Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 10–20% of Caucasian and at least 50% of Asian non-small cell lung cancer (NSCLC) patients [1,2,3,4]
In 2018 the FDA approved the second-generation EGFR tyrosine kinase inhibitors (EGFRi) afatinib for treatment of S768I, L861Q and G719X rare EGFR point mutations based on evidence from pooled analysis of three clinical trials, LUX-Lung 2, LUX-Lung 3 and LUX-Lung 6 [9,10]
Retrospective analysis of EGFR mutant NSCLC patients treated with pembrolizumab or nivolumab revealed that patients harbouring G719X and exon 20 insertion mutations have longer median progression-free survival (PFS) compared to patients harbouring classical mutations (8.4 months vs 1.6 months; Yamada et al, 2019)
Summary
Activating mutations in the epidermal growth factor receptor (EGFR) gene occur in 10–20% of Caucasian and at least 50% of Asian non-small cell lung cancer (NSCLC) patients [1,2,3,4]. One obstacle to understanding the differences in biology of rare EGFR mutations compared to classical EGFR mutations is the lack of patient-derived NSCLC cell line models that harbour endogenous rare EGFR mutations. Many preclinical studies rely on exogenous expression of rare EGFR mutants in model cell lines such as the mouse pro-B cell line Ba/F3 and mouse fibroblast cell line NIH-3T3. Despite these limitations, structural and preclinical data have been used to predict the efficacy of different EGFRi for specific rare EGFR mutations. We describe the structural features of rare EGFR mutations and elaborate on the preclinical and clinical evidence for EGFRi response for patients that harbour such rare EGFR mutations
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