Journal Article

DKFZ-2026-00026

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PET/CT-Guided Management of Immune Checkpoint Blockade and Post-Treatment Multi-Modal Profiling in Long-Term Responders with Metastatic Lung Cancer in the National Network Genomic Medicine Lung Cancer Germany (nNGM).

Frost, N. ; Joosten, M. ; Franzen, J. ; Wiesweg, M. ; Rasokat, A. ; Kulhavy, J. ; Kollmeier, J. ; Reinmuth, N. ; Grohé, C. ; Roeper, J. ; Rittmeyer, A. ; Heinzen, S. ; Wermke, M. ; Wesseler, C. ; Christopoulos, P. ; Kauffmann-Guerrero, D. ; Althoff, A. ; Bleckmann, A. ; Collienne, M.DKFZ* ; Berezucki, E. ; Overbeck, T. ; Kropf-Sanchen, C.DKFZ* ; Griesinger, F. ; Sebastian, M. ; Schuler, M. ; Braun, S. ; Wenzel, C. ; Furth, C. ; Wolf, J. ; Bischoff, P.DKFZ* ; Reck, M. ; Germany, N. N. G. M. L. C. (Collaboration Author) ; Frost, N. (Contributor)DKFZ* ; Joosten, M. (Contributor) ; Franzen, J. (Contributor) ; Wiesweg, M. (Contributor) ; Rasokat, A. (Contributor) ; Kulhavy, J. (Contributor) ; Kollmeier, J. (Contributor) ; Reinmuth, N. (Contributor) ; Grohé, C. (Contributor) ; Röper, J. (Contributor) ; Rittmeyer, A. (Contributor) ; Heinzen, S. (Contributor) ; Wermke, M. (Contributor) ; Wesseler, C. (Contributor) ; Christopoulos, P. (Contributor) ; Kauffmann-Guerrero, D. (Contributor) ; Althoff, A. (Contributor) ; Bleckmann, A. (Contributor) ; Collienne, M. (Contributor)DKFZ* ; Berezucki, E. (Contributor) ; Overbeck, T. (Contributor) ; Kropf-Sanchen, C. (Contributor)DKFZ* ; Griesinger, F. (Contributor) ; Sebastian, M. (Contributor) ; Schuler, M. (Contributor) ; Braun, S. (Contributor) ; Wenzel, C. (Contributor) ; Furth, C. (Contributor) ; Wolf, J. (Contributor) ; Bischoff, P. (Contributor)DKFZ* ; Reck, M. (Contributor) ; Hilbrandt, M. (Contributor) ; Horst, D. (Contributor) ; Hummel, H.-D. (Contributor) ; Kemper, M. (Contributor) ; Kron, A. (Contributor) ; Loges, S. (Contributor)DKFZ* ; Lüders, H. (Contributor) ; Ochsenreither, S. (Contributor)DKFZ* ; Raspe, M. (Contributor) ; Saalfeld, F. (Contributor) ; Schulz, C. (Contributor) ; Terrahe, S. (Contributor) ; Thomas, M. (Contributor) ; Wild, P. J. (Contributor)

2025
Elsevier Amsterdam [u.a.]

Abstract: The optimal duration of immune checkpoint blockade (ICB) in lung cancer remains undefined. Indefinite treatment in long-term responders increases healthcare burden, exposes patients to avoidable toxicities, and is not supported by any clinical and biological rationale or translational data. Prospective strategies to determine the optimal duration of immunotherapy in lung cancer are urgently needed.In this retrospective cohort study, 455 patients from 21 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 TIL quantification, and spatial transcriptomics to explore mechanisms of late resistance.After a median follow-up of 55 months, cohort A showed significantly longer OS (median not reached vs. 82 months; HR 0.35 [0.18-0.67], p = 0.002), despite substantially shorter treatment duration (27 vs. 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) vs. 17% (B). Post-treatment tumors exhibited features of acquired resistance, whereas SPLC displayed characteristics of primary resistance, including low PD-L1 expression, low TMB, and immunologically cold tumor microenvironments.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.

Keyword(s): Lung cancer ; discontinuation ; immune checkpoint blockade ; long-term response ; resistance mechanisms ; second primary lung cancer

Note: epub

---

Contributing Institute(s):

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

Research Program(s):

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

Appears in the scientific report 2025

---

Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 50 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---