Impact of <i>TP53</i> Mutations on Outcome in <i>EGFR</i> -Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors

Abstract

<b>Purpose:</b> To analyze the impact of <i>TP53</i> mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with <i>EGFR</i>-mutated non-small cell lung cancer (NSCLC).<b>Experimental Design:</b> 136 <i>EGFR</i>-mutated NSCLC patients receiving first-line TKIs were analyzed. <i>TP53</i> mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).<b>Results:</b><i>TP53</i> mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in <i>TP53</i>-mutated patients compared with 88% in <i>TP53</i>-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), <i>P</i> = 0.019]. In particular, a 42% DCR was observed in patients with <i>TP53</i> exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), <i>P</i> < 0.001]. Shorter median PFS and OS were observed in patients with <i>TP53</i> exon 8 mutations compared with others (4.2 vs. 12.5, <i>P</i> = 0.058, and 16.2 vs. 32.3, <i>P</i> = 0.114, respectively); these differences became significant in the subgroup with <i>EGFR</i> exon 19 deletion (4.2 vs. 16.8, <i>P</i> < 0.001, and 7.6 vs. not reached, <i>P</i> = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, <i>P</i> < 0.001) and HR 4.75 (95% CI, 1.38-16.29, <i>P</i> = 0.013), respectively.<b>Conclusions:</b><i>TP53</i> mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in <i>EGFR</i>-mutated NSCLC patients, mainly those carrying exon 19 deletions. <i>Clin Cancer Res; 23(9); 2195-202. ©2016 AACR</i>.