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

Philip Bischoff; Martin Reck; Tobias Overbeck; Petros Christopoulos; Achim Rittmeyer; Heike Lüders; Jens Kollmeier; Jonas Kulhavy; Marcel Kemper; Niels Reinmuth; Julia Röper; Melanie Janning; Linna Sommer; Lukas Aguinarte; Myriam Koch; Marcel Wiesweg; Claas Wesseler; Cornelius F Waller; Diego Kauffmann-Guerrero; Albrecht Stenzinger; Susann Stephan-Falkenau; Marcel Trautmann; Silke Lassmann; Markus Tiemann; Frederick Klauschen; Martin Sebastian; Frank Griesinger; Jürgen Wolf; Sonja Loges; Nikolaj Frost; National Network Genomic Medicine Lung Cancer (nNGM) Collaborator Group

doi:10.1016/j.jtho.2023.12.015

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

J Thorac Oncol. 2023 Dec 13:S1556-0864(23)02423-1. doi: 10.1016/j.jtho.2023.12.015. Online ahead of print.

Authors

Philip Bischoff¹, Martin Reck², Tobias Overbeck³, Petros Christopoulos⁴, Achim Rittmeyer⁵, Heike Lüders⁶, Jens Kollmeier⁷, Jonas Kulhavy⁸, Marcel Kemper⁹, Niels Reinmuth¹⁰, Julia Röper¹¹, Melanie Janning¹², Linna Sommer¹³, Lukas Aguinarte¹⁴, Myriam Koch¹⁵, Marcel Wiesweg¹⁶, Claas Wesseler¹⁷, Cornelius F Waller¹⁸, Diego Kauffmann-Guerrero¹⁹, Albrecht Stenzinger²⁰, Susann Stephan-Falkenau²¹, Marcel Trautmann²², Silke Lassmann²³, Markus Tiemann²⁴, Frederick Klauschen²⁵, Martin Sebastian¹⁴, Frank Griesinger¹¹, Jürgen Wolf²⁶, Sonja Loges¹⁶, Nikolaj Frost²⁷; National Network Genomic Medicine Lung Cancer (nNGM) Collaborator Group

Collaborators

National Network Genomic Medicine Lung Cancer (nNGM) Collaborator Group:
Moritz Hilbrandt²⁸, Juliane Süptitz²⁶, Christian Grah²⁹, Janna-Lisa Velthaus³⁰, Hans-Georg Kopp³¹, Bernd Schmidt²⁸, Susanne Horter³², Stefanie Keymel³³, Enver Aydilek³, Guergana Tritchkova¹³, Matthias Raspe²⁸, Dražen Papić³⁴, Stefan Florian³⁴, David Horst³⁵, Peter J Wild³⁶, Michael Thomas⁴, Christian Grohé⁶, Annalen Bleckmann⁹, Martin Wermke¹³, Horst-Dieter Hummel⁸, Jan Stratmann¹⁴, Wolfgang Schütte²⁸

Affiliations

¹ Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany; BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany; German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Lung Clinic Grosshansdorf, Airway Research Center North, German Center of Lung Research, Grosshansdorf, Germany.
³ Department of Haematology and Medical Oncology, University Medical Center Göttingen and Lungentumorzentrum Universität Göttingen, Göttingen, Germany.
⁴ Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
⁵ Department of Thoracic Oncology, LKI Lungenfachklinik Immenhausen, Immenhausen, Germany.
⁶ Klinik für Pneumologie-Evangelische Lungenklinik Berlin Buch, Berlin, Germany.
⁷ Helios Klinikum Emil von Behring, Lungenklinik Heckeshorn, Berlin, Germany; Berlin Lung Institute, Berlin, Germany.
⁸ Translational Oncology/Early Clinical Trial Unit (ECTU), Comprehensive Cancer Center Mainfranken and Bavarian Cancer Research Center (BZKF), University Hospital Wuerzburg, Wuerzburg, Germany.
⁹ Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.
¹⁰ Asklepios Lung Clinic, member of the German Center for Lung Research (DZL), Munich-Gauting, Germany.
¹¹ Department of Hematology and Oncology, Pius-Hospital, University Dept. of Internal Medicine-Oncology, Oldenburg, Germany.
¹² DKFZ-Hector Cancer Institute and Department of Personalized Oncology at the University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), German Center for Lung Research (DZL), Heidelberg, Germany.
¹³ Department of Thoracic Oncology, Carl-Gustav-Carus Dresden University Hospital, Dresden, Germany.
¹⁴ Hematology/Oncology, Department of Medicine II, University Hospital Frankfurt, Frankfurt, Germany.
¹⁵ University Hospital Regensburg, Department of Internal Medicine 2, Regensburg, Germany.
¹⁶ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
¹⁷ Department of Thoracic Oncology, Asklepios Klinikum Harburg, Hamburg, Germany.
¹⁸ Department of Haematology, Oncology and Stem Cell Transplantation, University Medical Centre Freiburg and Faculty of Medicine, Freiburg, Germany.
¹⁹ Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL-CPCM), Munich, Germany.
²⁰ Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
²¹ Department of Tissue Diagnostics, Helios Klinikum Emil von Behring, Berlin, Germany.
²² University of Münster, Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, Münster University Hospital, Münster, Germany.
²³ Institute for Surgical Pathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁴ Institute for Hematopathology, Hamburg, Germany.
²⁵ Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany; Berlin Institute for the Foundation of Learning and Data (BIFOLD) and Charité-Universitätsmedizin Berlin, Berlin, Germany.
²⁶ Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
²⁷ Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin (Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health), Berlin, Germany. Electronic address: Nikolaj.frost@charite.de.
²⁸ Department of Respiratory Medicine, DRK Kliniken Berlin Mitte, Berlin, Germany.
²⁹ Department of Internal Medicine and Respiratory Medicine, Clinic Havelhöhe Berlin, Berlin, Germany.
³⁰ Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
³¹ Robert Bosch Centrum für Tumorerkrankungen Stuttgart, Stuttgart, Germany.
³² Clinic of Internal Medicine, Hospital Martha-Maria Halle-Dölau, Halle, Germany.
³³ Department of Cardiology, Pneumology and Angiology, Medical Faculty, University Hospital Dusseldorf, Dusseldorf, Germany.
³⁴ Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, Berlin Institute of Health at Charité - Universitätsmedizin Berlin.
³⁵ Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany, Berlin Institute of Health at Charité - Universitätsmedizin Berlin; German Cancer Consortium (DKTK), partner site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt, Germany.

PMID: 38096950
DOI: 10.1016/j.jtho.2023.12.015

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 efficacy 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 KRASmut and TP53mut was 53% (G12C 25%, non-G12C 28%) and 51%, respectively. In KRASmut patients, TP53 comutations increased response rates (G12C: 69.7% versus 46.5% [TP53mut versus wild-type (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 KRASwt patients. After a median follow-up of 41 months, G12C/TP53mut 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 non-G12C and KRASwt, 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.

Keywords: Checkpoint inhibitor; KRAS; NSCLC; Predictive biomarker; TP53.