The significance of co-mutations in EGFR-mutated non-small cell lung cancer: Optimizing the efficacy of targeted therapies?

: Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide. In non-squamous NSCLC, the identification of oncogenic drivers and the development of target-specific molecules led to remarkable progress in therapeutic strategies and overall survival over the last decade. Nevertheless, responses are limited by systematically acquired mechanisms of resistance early on after starting a targeted therapy. Moreover, mounting evidence has demonstrated that each oncogenic-driven cluster is actually heterogeneous in terms of molecular features, clinical behaviour, and sensitivity to targeted therapy. In this review, we aimed to examine the prognostic and predictive significance of oncogene-driven co-mutations, focusing mainly on EGFR and TP53. A narrative review was performed by searching MEDLINE databases for English articles published over the last decade (from January 2012 until November 2022). The bibliographies of key references were manually reviewed to select those eligible for the topic. The genetic landscape of EGFR-mutated NSCLC is more complicated than what is known so far. In particular, the occurrence of TP53 co-mutations stratify patients carrying EGFR mutations in terms of treatment response. The study provides a deeper understanding of the mechanisms underlying the variability of the genetic landscape of EGFR-mutated NSCLC and summarizes notably the clinical importance of TP53 co-mutations for an open avenue to more properly addressing the clinical decision-making in the near future.