**Concomitant** *TP53* **Mutation Confers Worse Prognosis in** *EGFR***-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs**

**Matteo Canale 1, Elisabetta Petracci 2, Angelo Delmonte 3, Giuseppe Bronte 3, Elisa Chiadini 1, Vienna Ludovini 4, Alessandra Dubini 5, Maximilian Papi 6, Sara Baglivo 4, Nicoletta De Luigi 7, Alberto Verlicchi 3, Rita Chiari 8, Lorenza Landi 9, Giulio Metro 4, Marco Angelo Burgio 3, Lucio Crinò <sup>3</sup> and Paola Ulivi 1,\***


Received: 2 March 2020; Accepted: 3 April 2020; Published: 7 April 2020

**Abstract:** Background: Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths worldwide. Epidermal Growth Factor Receptor (*EGFR*)-mutated patients usually benefit from TKIs treatment, but a significant portion show unresponsiveness due to primary resistance mechanisms. We investigated the role of *TP53* mutations in predicting survival and response to *EGFR*-TKIs in EGFR-mutated NSCLC patients, to confirm, on an independent case series, our previous results. Methods: An independent retrospective cohort study was conducted, on a case series of 136 *EGFR*-mutated NSCLC patients receiving first or second generation TKIs as a first line therapy, and a smaller fraction of patients who acquired the T790M resistance mutation and were treated with third generation TKIs in the second or further line of treatment. *TP53* mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) of the patients. Results: Forty-two patients (30.9%) showed a *TP53* mutation. Considered together, *TP53* mutations had no significant impact on time-to-event endpoints. Considering the different *TP53* mutations separately, exon 8 mutations confirmed their negative effect on PFS (HR 3.16, 95% 1.59–6.28, *p* = 0.001). In patients who developed the T790M resistance mutation, treated with third generation TKIs, the *TP53* exon 8 mutations predicted worse PFS (even though not statistically significant), and OS (HR 4.86, 95% CI: 1.25–18.90, *p* = 0.023). Conclusions: *TP53* exon 8 mutations confirmed their negative prognostic impact in patients treated with first and second generation TKIs and demonstrated a role in affecting clinical outcome in patients treated with third generation TKIs.

**Keywords:** non-small-cell lung cancer; epidermal growth factor receptor; tyrosine kinase inhibitors; *TP53* mutations; responsiveness; prognosis
