**2. Materials and Methods**

To confirm our previous results on the role of *TP53* mutations in relation to the effectiveness of TKIs, an independent retrospective cohort study was conducted. All consecutive patients with advanced *EGFR*-mutated NSCLC receiving a first line TKI treatment (i.e., gefitinib, erlotinib, or afatinib) from July 2010 to May 2018 at the Medical Oncology Units of the Romagna catchment area (Area Vasta Romagna, AVR) and at the S. Maria della Misericordia Hospital of Perugia, Italy, were included in this study. Demographic and clinical characteristics of the patients were obtained using a medical and radiographic records review including age, gender, smoking history, histology, and information on death and response to treatment. *EGFR* status had been routinely determined at the Biosciences Laboratory of IRST-IRCCS and the Laboratory of Molecular Biology of the S. Maria della Misericordia Hospital, Perugia, by MassARRAY, pyrosequencing, direct sequencing or Next-Generation Sequencing (NGS) methodologies.

To evaluate the independent role of *TP53* mutations, that is, eventually adjusting for other covariates, and to obtain a more accurate estimate of their prognostic effect, an analysis combining the data of the present work with those from our previous one [6], was also performed, updating follow-ups of the previous case series to 30 June 2018.

Moreover, considering the two cohorts together, we identified a subgroup of 42 patients who developed the T790M resistance mutation and were treated with third generation TKI, osimertinib. All patients provided an informed consent, and the study was approved by the AVR Ethical Committee (study code IRST-B053).
