Bischoff, Philip and Reck, Martin and Overbeck, Tobias and Christopoulos, Petros and Rittmeyer, Achim and Lueders, Heike and Kollmeier, Jens and Kulhavy, Jonas and Kemper, Marcel and Reinmuth, Niels and Roeper, Julia and Janning, Melanie and Sommer, Linna and Aguinarte, Lukas and Koch, Myriam and Wiesweg, Marcel and Wesseler, Claas and Waller, Cornelius F. and Kauffmann-Guerrero, Diego and Stenzinger, Albrecht and Stephan-Falkenau, Susann and Trautmann, Marcel and Lassmann, Silke and Tiemann, Markus and Klauschen, Frederick and Sebastian, Martin and Griesinger, Frank and Wolf, Juergen and Loges, Sonja and Frost, Nikolaj (2024) Outcome of First-Line Treatment With Pembrolizumab According to KRAS / TP53 Mutational Status for Nonsquamous Programmed Death-Ligand 1-High (≥50%) NSCLC in the German National Network Genomic Medicine Lung Cancer. JOURNAL OF THORACIC ONCOLOGY, 19 (5). pp. 803-817. ISSN 1556-0864, 1556-1380
Full text not available from this repository. (Request a copy)Abstract
Introduction: Programmed death-ligand 1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic NSCLC in the clinical routine, but it has limited value in distinguishing responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap. Methods: A total of 696 consecutive patients with programmed death-ligand 1 -high (>= 50%), nonsquamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with Eastern Cooperative Oncology Group performance status less than or equal to 1 and pembrolizumab as first-line palliative treatment, were included into this retrospective cohort analysis. Treatment ef ficacy and outcome according to KRAS / TP53 status were correlated with TME composition and gene expression analysis of The Cancer Genome Atlas lung adenocarcinoma cohort. Results: Proportion of KRAS mut and TP53 mut was 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRAS mut patients, TP53 comutations increased response rates (G12C: 69.7% versus 46.5% [ TP53 mut versus wildtype (wt)], p = 0.004; non-G12C: 55.4% versus 39.5%, p = 0.03), progression-free survival (G12C: hazard ratio [HR] = 0.59, p = 0.009, non-G12C: HR = 0.7, p = 0.047), and overall survival (G12C: HR = 0.72, p = 0.16, non-G12C: HR = 0.56, p = 0.002), whereas no differences were observed in KRAS wt patients. After a median follow-up of 41 months, G12C/ TP53 mut patients experienced the longest progression-free survival and overall survival (33.7 and 65.3 mo), which correlated with high tumor-infiltrating lymphocyte densities in the TME and up-regulation of interferon gamma target genes. Proinflammatory pathways according to TP53 status (mut versus wt) were less enhanced and not different in nonG12C and KRAS wt, respectively. Conclusions: G12C/ TP53 comutations identify a subset of patients with a very favorable long-term survival with immune checkpoint inhibitor monotherapy, mediated by highly active interferon gamma signaling in a proinflammatory TME. (c) 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PD-L1 EXPRESSION; TP53 MUTATIONS; SURVIVAL; IMMUNOTHERAPY; CHEMOTHERAPY; EFFICACY; NSCLC; Checkpoint inhibitor; KRAS; TP53; Pre- dictive biomarker |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Jul 2025 09:25 |
| Last Modified: | 24 Jul 2025 09:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65725 |
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