**1. Introduction**

Epidermal growth factor receptor (*EGFR*)-tyrosine kinase inhibitors (TKIs) have changed the natural history of non-small-cell lung cancer (NSCLC) patients harboring specific *EGFR* mutations at exons 18, 19 and 21. Randomized trials have demonstrated a median progression-free survival (PFS) of 9.7 and 9.5 months in patients harboring sensitizing *EGFR* mutations treated with first-generation *EGFR*-TKIs versus platinum-based chemotherapy [1,2], and 11.1 months for second generation TKIs [3]. Third generation TKI osimertinib, initially designed to overcome the arising of T790M resistance mutation in *EGFR* pre-treated patients [4], has recently become the gold standard for *EGFR*-mutated patients, reaching a median PFS of 18.9 months [5].

Despite the high sensitivity of *EGFR*-mutated patients to *EGFR*-TKIs, the objective response rate is of about 70–80% for 1st, 2nd and 3rd generation TKIs [2,3,5], meaning that a portion of patients do not respond to *EGFR*-TKI treatment, notwithstanding the presence of sensitizing *EGFR* mutation, suggesting the presence of primary resistance mechanisms.

Our previous study and several others showed that the concomitant presence of *TP53* mutation confers a worse prognosis in *EGFR*-mutated patients treated with first and second generation TKIs [6–8]. Subsequent studies performed using next generation sequencing methodologies showed that the presence of concomitant mutation in different genes is associated with a lower response to *EGFR-*TKIs and, however, *TP53* mutation confirms to be the most significant predictor of worse outcome. In particular, it seems that specific *TP53* mutations are more implicated in predicting the worse prognosis [6,9,10], confirming that different *TP53* mutations confer different p53 functions. Within the coding region of the *TP53* gene, several studies have reported that a higher frequency of mutations occurs in the exons 5–8, and that mutations in these exons are associated to differential functions of p53 protein [9,10]. As the different published studies have analyzed principally patients treated with first and second generation TKIs, few data are available with regard to the role of *TP53* mutation in relation to response to third generation TKIs.

The main purpose of this research was to confirm our previously published results on the role of *TP53* mutations, in an independent cohort of advanced *EGFR*-mutated patients treated with first or second generation TKIs in the first line setting, and to investigate the role of *TP53* mutations in predicting prognosis of patients with acquired T790M mutation treated with third generation TKIs.
