TP53 mutations predicts worse prognosis in EGFR-mutated NSCLC patients receiving TKIs in first- or further line of treatment

Abstract

Background: Non-small cell lung cancer (NSCLC) patients carrying epidermal growth factor receptor (EGFR) mutations are sensitive to tyrosine kinase inhibitors (TKIs); nonetheless, about 20% of patients show primary resistance to TKIs. We previously demonstrated the association between TP53 mutations and primary resistance to firstline TKIs in EGFR-mutated adenocarcinoma (ADC) patients. Here we analyze a validation case series of ADC patients treated with first-line TKIs to confirm our previous data, and we assess the association between TP53 status and the prognosis of ADC patients treated with third generation TKIs. Methods: We considered 136 ADC EGFR-mutated patients treated with a TKI in the first-line setting. Also, we analyzed 42 patients who developed T790M mutation and were treated with a third generation TKI in second-or further line setting. EGFR and TP53 mutation analyses were performed by Sanger Sequencing or Next Generation Sequencing methodologies. TP53 mutations were evaluated in relation to disease control rate (DCR: complete response [CR], partial response [PR] or stable disease [SD]), objective response rate (ORR: CR, PR), progression-free survival (PFS) and overall survival (OS). Results: of 136 patients, we found 42 (31%) TP53 mutations: 12 mutations in exon 5 (28.6%), 6 in exon 6 (14.3%), 13 in exon 7 (30.9%), and 11 in exon 8 (26.2%). DCR and ORR were 31.8% and 32.5% in TP3-mutated patients with respect to 68.6% and 67.4% in TP53 wild-type (wt) patients, respectively. Exon 8 TP53-mutated patients had a worse PFS with respect to TP53 wt patients (HR 3.19 [1.62-6.27], p=0.001), but not OS. Moreover, we assessed TP53 status in 42 patients who developed a T790M mutation and received a third generation TKI in second or additional lines of treatment. In 30 patients with evaluable clinical response, DCR and ORR were 62.5% and 25% in TP53 mutated patients, with respect to 77.2% and 54.5% in the TP53 wt patients, respectively. Data analyses of PFS and OS are ongoing. Conclusions: EGFR-mutated NSCLC patients with concomitant TP53 mutations had a worse clinical response to first-, second-, and third generation TKIs, administrated in any line of treatment.