• Lung Cancer · Jun 2019

    Association of TP53 mutations with response and longer survival under immune checkpoint inhibitors in advanced non-small-cell lung cancer.

    • Sandra Assoun, Nathalie Theou-Anton, Marina Nguenang, Aurélie Cazes, Claire Danel, Baptiste Abbar, Johan Pluvy, Valérie Gounant, Antoine Khalil, Céline Namour, Solenn Brosseau, and Gérard Zalcman.
    • Thoracic Oncology Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France; U830 INSERM "Genetics and biology of cancers", Research Centre, Institut Curie, 26 rue d'Ulm, 75005, Paris, France.
    • Lung Cancer. 2019 Jun 1; 132: 65-71.

    IntroductionTumor mutational burden (TMB) correlates with response to immune checkpoint inhibitors (ICI) in advanced non-small-cell lung cancer (aNSCLC). We hypothesized that TP53 mutations could reflect TMB and be associated with ICI benefit.MethodsTP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with programmed death-1 (PD-1) blockers. Clinical data, tumor programmed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS).ResultsIn total, 72 patients (median [interquartile range] age: 61 [33-83] years) were included; 52 (72%) were male; 39 (54%) had performance status 0-1; 53 (74%) had adenocarcinoma; 20 (28%) received first-line ICI, 52 (72%) second line or more. In 65 patients with available data, 36 (55%) expressed PD-L1 in ≥50% of tumor cells, 20 (31%) in 1-49% of cells, and nine (14%) were PD-L1-negative. Non-synonymous TP53 mutations were observed in 41 (57%) and 25 (35%) harbored KRAS-mutated tumors. After a median follow-up of 15.2 months (95% confidence interval [CI] 10.3-17.4 m), the median OS in the TP53-mutated group was 18.1 months (95% CI 6.6-not reached), vs. 8.1 months (95% CI 2.2-14.5, hazard ratio [HR] = 0.48; 95% CI 0.25-0.95, p = 0.04) in the TP53-wild-type group. Median progression-free survival was significantly longer in TP53-mutated patients (4.5 months, 95% CI 2.8-18.1 versus 1.4, 95% CI 1.1-3.5; p = 0.03), although TP53 mutation status failed to significantly influence PFS in the multivariate analysis (p = 0.32). Objective response rate (ORR) was higher in patients with TP53 mutation (51.2% vs. 20.7%; p = 0.01). In multivariate analysis, TP53 mutations independently associated with longer OS (HR = 0.35, 95% CI 0.16-0.77, p = 0.009).ConclusionsTP53-mutated status correlated with immunotherapy OS benefit in aNSCLC.Copyright © 2019 Elsevier B.V. All rights reserved.

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