Sandra Assoun1, Nathalie Theou-Anton2, Marina Nguenang3, Aurélie Cazes4, Claire Danel4, Baptiste Abbar3, Johan Pluvy3, Valérie Gounant3, Antoine Khalil5, Céline Namour3, Solenn Brosseau6, Gérard Zalcman7. 1. 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. 2. Genetics Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France. 3. Thoracic Oncology Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France. 4. Pathology Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France. 5. Radiology Department, University Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France. 6. 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; Medicine Faculty, University Paris-Diderot, 46 rue Henri Huchard, 75018 Paris, France. 7. 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; Medicine Faculty, University Paris-Diderot, 46 rue Henri Huchard, 75018 Paris, France. Electronic address: gerard.zalcman@aphp.fr.
Abstract
INTRODUCTION: Tumor 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. METHODS: TP53 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). RESULTS: In 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). CONCLUSIONS: TP53-mutated status correlated with immunotherapy OS benefit in aNSCLC.
INTRODUCTION:Tumor 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. METHODS:TP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with programmed death-1 (PD-1) blockers. Clinical data, tumorprogrammed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS). RESULTS: In 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). CONCLUSIONS:TP53-mutated status correlated with immunotherapy OS benefit in aNSCLC.
Authors: Sarah Abou Alaiwi; Amin H Nassar; Wanling Xie; Ziad Bakouny; Jacob E Berchuck; David A Braun; Sylvan C Baca; Pier Vitale Nuzzo; Ronan Flippot; Tarek H Mouhieddine; Liam F Spurr; Yvonne Y Li; Taiwen Li; Abdallah Flaifel; John A Steinharter; Claire A Margolis; Natalie I Vokes; Heng Du; Sachet A Shukla; Andrew D Cherniack; Guru Sonpavde; Robert I Haddad; Mark M Awad; Marios Giannakis; F Stephen Hodi; X Shirley Liu; Sabina Signoretti; Cigall Kadoch; Matthew L Freedman; David J Kwiatkowski; Eliezer M Van Allen; Toni K Choueiri Journal: Cancer Immunol Res Date: 2020-04-22 Impact factor: 11.151