Journal Article

DKFZ-2023-02728

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Outcome of first-line treatment with pembrolizumab according to KRAS/TP53 mutational status for non-squamous PD-L1 high (≥50%) NSCLC in the German National Network Genomic Medicine Lung Cancer (nNGM).

Bischoff, P.DKFZ* ; Reck, M. ; Overbeck, T. ; Christopoulos, P. ; Rittmeyer, A. ; Lüders, H. ; Kollmeier, J. ; Kulhavy, J. ; Kemper, M. ; Reinmuth, N. ; Röper, J. ; Janning, M.DKFZ* ; Sommer, L. ; Aguinarte, L. ; Koch, M. ; Wiesweg, M. ; Wesseler, C. ; Waller, C. F. ; Kauffmann-Guerrero, D. ; Stenzinger, A. ; Stephan-Falkenau, S. ; Trautmann, M. ; Lassmann, S. ; Tiemann, M. ; Klauschen, F. ; Sebastian, M. ; Griesinger, F. ; Wolf, J. ; Loges, S. ; Frost, N. ; Cancer, N. N. G. M. L. (Collaboration Author)

2024
Elsevier Amsterdam

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Please use a persistent id in citations: doi:10.1016/j.jtho.2023.12.015

Abstract: PD-L1 expression currently represents the only validated predictive biomarker for immune checkpoint inhibition in metastatic non-small cell lung cancer (NSCLC) in the clinical routine, but has limited value to distinguish responses. Assessment of KRAS and TP53 mutations (mut) as surrogate for an immunosupportive tumor microenvironment (TME) might help to close this gap.696 consecutive patients with PD-L1 high (≥50%), non-squamous NSCLC, having received molecular testing within the German National Network Genomic Medicine Lung Cancer between 2017 and 2020, with ECOG-PS ≤1 and pembrolizumab as first-line palliative treatment were included into this retrospective cohort analysis. Treatment efficacy and outcome according to KRAS/TP53 status were correlated with TME composition and gene expression analysis of the TCGA lung adenocarcinoma cohort.Proportion of KRASmut and TP53mut were 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRASmut patients, TP53 co-mutations increased response rates (G12C: 69.7% vs. 46.5% (TP53mut vs. wt), p=0.004; non-G12C: 55.4% vs. 39.5%, p=0.03), progression-free (PFS; G12C: HR 0.59, p=0.009, non-G12C: HR 0.7, p=0.047) and overall survival (OS; G12C: HR 0.72, p=0.16, non-G12C: HR 0.56, p=0.002), whereas no differences were observed in KRASwt patients. After a median follow-up of 41 months, G12C/TP53mut patients experienced the longest PFS and OS (33.7 and 65.3 months), correlated with high TIL densities in the TME and upregulation of IFNγ target genes. Pro-inflammatory pathways according to TP53 status (mut vs. wt) were less enhanced and not different in non-G12C and KRASwt, respectively.G12C/TP53 co-mutations identify a subset of patients with a very favorable long-term survival with ICI monotherapy, mediated by highly active IFNγ signaling in a pro-inflammatory TME.

Keyword(s): KRAS ; NSCLC ; TP53 ; checkpoint inhibitor ; predictive biomarker

Note: 2024 May;19(5):803-817

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)
2. Personalisierte Medizinische Onkologie (A420)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2023

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Database coverage:
; Allianz-Lizenz ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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