PET/CT-guided management of immune checkpoint blockade and multi-modal profiling following treatment in long-term responders with metastatic lung cancer in the National Network Genomic Medicine Lung Cancer Germany (nNGM)

N Frost; M Joosten; J Franzen; M Wiesweg; A Rasokat; J Kulhavy; J Kollmeier; N Reinmuth; C Grohé; J Roeper; A Rittmeyer; S Heinzen; M Wermke; C Wesseler; P Christopoulos; D Kauffmann-Guerrero; A Althoff; A Bleckmann; M Collienne; E Berezucki; T Overbeck; C Kropf-Sanchen; F Griesinger; M Sebastian; M Schuler; S Braun; C Wenzel; C Furth; J Wolf; P Bischoff; M Reck; National Network Genomic Medicine Lung Cancer Germany

doi:10.1016/j.annonc.2025.12.011

PET/CT-guided management of immune checkpoint blockade and multi-modal profiling following treatment in long-term responders with metastatic lung cancer in the National Network Genomic Medicine Lung Cancer Germany (nNGM)

Ann Oncol. 2025 Dec 30:S0923-7534(25)06329-X. doi: 10.1016/j.annonc.2025.12.011. Online ahead of print.

Authors

N Frost¹, M Joosten², J Franzen³, M Wiesweg⁴, A Rasokat⁵, J Kulhavy⁶, J Kollmeier⁷, N Reinmuth⁸, C Grohé⁹, J Roeper¹⁰, A Rittmeyer¹¹, S Heinzen¹², M Wermke¹³, C Wesseler¹⁴, P Christopoulos¹⁵, D Kauffmann-Guerrero¹⁶, A Althoff¹⁷, A Bleckmann¹⁸, M Collienne¹⁹, E Berezucki²⁰, T Overbeck²¹, C Kropf-Sanchen²², F Griesinger¹⁰, M Sebastian¹², M Schuler⁴, S Braun²³, C Wenzel²⁴, C Furth²⁵, J Wolf⁵, P Bischoff²⁶, M Reck²⁷; National Network Genomic Medicine Lung Cancer Germany

Affiliations

¹ 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; National Center for Tumor Diseases (NCT), NCT Berlin, Berlin, Germany. Electronic address: Nikolaj.frost@charite.de.
² 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.
³ 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; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association and Helmholtz Imaging, Berlin, Germany; Digital Engineering Faculty, University of Potsdam, Potsdam, Germany.
⁴ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; National Center for Tumor Diseases (NCT), NCT West, Essen, Germany.
⁵ Department I of Internal Medicine, Center for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
⁶ Translational Oncology/Early Clinical Trial Unit (ECTU), Comprehensive Cancer Center Mainfranken and Bavarian Cancer Research Center (BZKF), University Hospital Wuerzburg, Wuerzburg, Germany.
⁷ Helios Klinikum Emil von Behring, Lungenklinik Heckeshorn, Berlin, Germany; Berlin Lung Institute, Berlin, Germany.
⁸ Asklepios Lung Clinic, Member of the German Center for Lung Research (DZL), Munich-Gauting, Germany.
⁹ Klinik für Pneumologie-Evangelische Lungenklinik Berlin Buch, Berlin, Germany.
¹⁰ Department of Hematology and Oncology, Pius-Hospital, University Dept. of Internal Medicine - Oncology, Oldenburg, Germany.
¹¹ Department of Thoracic Oncology, LKI Lungenfachklinik Immenhausen, Immenhausen, Germany.
¹² Hematology/Oncology, Department of Medicine II, University Hospital Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany.
¹³ Department of Thoracic Oncology, Carl-Gustav-Carus Dresden University Hospital, Dresden, Germany.
¹⁴ Department of Thoracic Oncology, Asklepios Klinikum Harburg, Hamburg, Germany.
¹⁵ 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.
¹⁶ Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL- CPCM), Munich, Germany.
¹⁷ Department of Pulmonology, Thoraxzentrum Offenbach, Sana Klinikum Offenbach, Offenbach, Germany.
¹⁸ Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.
¹⁹ 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.
²⁰ Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.
²¹ Department of Hematology and Medical Oncology, University Medical Center Göttingen and Lungentumorzentrum Universität Göttingen, Göttingen, Germany.
²² 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; Division of Pulmonology, Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany.
²³ Institute of Pathology, Sana Clinic Offenbach GmbH, Offenbach, Germany.
²⁴ Institute for Pathology, University Hospital Carl-Gustav-Carus Dresden, Technische Universität Dresden, Dresden, Germany.
²⁵ Department of Nuclear Medicine, Charité Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
²⁶ 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; German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁷ Lung Clinic Großhansdorf, Airway Research Center North, German Center of Lung Research, Großhansdorf, Germany.

PMID: 41478526
DOI: 10.1016/j.annonc.2025.12.011

Abstract

Background: The optimal duration of immune checkpoint blockade (ICB) in lung cancer remains undefined. Indefinite treatment in long-term responders increases health care burden, exposes patients to avoidable toxicities, and is not supported by any clinical or biological rationale or translational data. Prospective strategies to determine the optimal duration of immunotherapy in lung cancer are urgently needed.

Patients and methods: In this retrospective cohort study, 455 patients from 21 National Network Genomic Medicine Lung Cancer Germany (nNGM) centers with ≥2 years of disease control on first-line ICB-based therapy were grouped into PET/CT-guided discontinuation (cohort A, n = 126) or continued ICB without PET/CT (cohort B, n = 329), and assessed for overall survival (OS). Matched pre- and post-ICB tumor samples from cohort A patients with persistent or progressive disease were analyzed by comprehensive genomic profiling, histological tumor-infiltrating lymphocyte quantification, and spatial transcriptomics to explore mechanisms of late resistance.

Results: After a median follow-up of 55 months, cohort A showed significantly longer OS [median not reached versus 82 months, hazard ratio 0.35 (95% confidence interval 0.18-0.67), P = 0.002], despite substantially shorter treatment duration (27 versus 45 months, P < 0.001). Discontinuation was either PET-driven (A) or resulted from immune-related toxicity, progression, or patients' choice (B). Systematic re-biopsies in cohort A revealed a high incidence of second primary lung cancers (SPLC, 28%). All progression events were managed exclusively with local (ablative) treatments in 53% (A) versus 17% (B). Tumors that occurred after treatment exhibited features of acquired resistance, whereas SPLC displayed characteristics of primary resistance, including low programmed death ligand 1 expression, low tumor mutational burden, and immunologically cold tumor microenvironments.

Conclusions: A structured discontinuation strategy appears to provide a safe approach for long-term ICB responders, enabling earlier detection of resistance before generalized progression. A confirmatory prospective non-inferiority randomized trial within the nNGM is underway.

Keywords: discontinuation; immune checkpoint blockade; long-term response; lung cancer; resistance mechanisms; second primary lung cancer.