*3.5. TP53 Mutations in Relation to Responsiveness to Third Generation TKIs: Combined Cohorts of Patients*

Considering both patients' cohorts (*n* = 272 patients), we considered 42 patients who developed a T790M resistance mutation and were treated with third generation TKI osimertinib, in the second or further lines of therapy. Of these, 41 were evaluable for *TP53* mutation status; we found 10 *TP53* mutated patients (24.4%): 3 mutations in exon 5 (30%), 1 in exon 6 (10%), 2 in exon 7 (20%) and 4 in exon 8 (40%). Within the 41 patients with available clinical information, median PFS and OS were 13.86 (95% CI: 5.5–18.53) and 44.38 months (95% CI: 10.64–24.28), respectively. Median PFS of exon 8 *TP53* mutated patients was 2.83 (2.17–NR) months, with respect to a median PFS of 16.79 (5.55–22.31) and 15.28 (1.91–NR) months, for wt *TP53* and patients with mutations in other exons of the gene, respectively (Figure 2A). Even though a good separation, the difference among curves was not statistically significant (*p* = 0.304), due to small numbers of the exon 8 mutated patients. On the other hand, exon 8 *TP53* gene mutations significantly affected the survival of the patients, with a median OS for exon 8 *TP53* mutated patients of 18.53 (7.26–NR) months, with respect to 42.15 (29.43–NR) and 59.92 (29.73–NR) months of patients with mutations in other exons of *TP53* and wt *TP53*, respectively (*p* = 0.044) (Figure 2B). Table 4 shows the univariate hazard ratios for PFS and OS with respect to the presence of *TP53* exon 8 mutation.

**Figure 2.** Progression-free survival (**A**) and Overall Survival (**B**) in relation to *TP53* mutations of patients with acquired T790M treated with third generation TKIs.


**Table 4.** *TP53* mutations in relation to progression-free survival (PFS) and overall survival (OS) of patients receiving osimertinib in second or further lines of treatment.
