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@ARTICLE{Frost:307521,
      author       = {N. Frost and M. Joosten and J. Franzen and M. Wiesweg and
                      A. Rasokat and J. Kulhavy and J. Kollmeier and N. Reinmuth
                      and C. Grohé and J. Roeper and A. Rittmeyer and S. Heinzen
                      and M. Wermke and C. Wesseler and P. Christopoulos and D.
                      Kauffmann-Guerrero and A. Althoff and A. Bleckmann and M.
                      Collienne$^*$ and E. Berezucki and T. Overbeck and C.
                      Kropf-Sanchen$^*$ and F. Griesinger and M. Sebastian and M.
                      Schuler and S. Braun and C. Wenzel and C. Furth and J. Wolf
                      and P. Bischoff$^*$ and M. Reck},
      collaboration = {N. N. G. M. L. C. Germany},
      othercontributors = {N. Frost$^*$ and M. Joosten and J. Franzen and M. Wiesweg
                          and A. Rasokat and J. Kulhavy and J. Kollmeier and N.
                          Reinmuth and C. Grohé and J. Röper and A. Rittmeyer and S.
                          Heinzen and M. Wermke and C. Wesseler and P. Christopoulos
                          and D. Kauffmann-Guerrero and A. Althoff and A. Bleckmann
                          and M. Collienne$^*$ and E. Berezucki and T. Overbeck and C.
                          Kropf-Sanchen$^*$ and F. Griesinger and M. Sebastian and M.
                          Schuler and S. Braun and C. Wenzel and C. Furth and J. Wolf
                          and P. Bischoff$^*$ and M. Reck and M. Hilbrandt and D.
                          Horst and H.-D. Hummel and M. Kemper and A. Kron and S.
                          Loges$^*$ and H. Lüders and S. Ochsenreither$^*$ and M.
                          Raspe and F. Saalfeld and C. Schulz and S. Terrahe and M.
                          Thomas and P. J. Wild},
      title        = {{PET}/{CT}-{G}uided {M}anagement of {I}mmune {C}heckpoint
                      {B}lockade and {P}ost-{T}reatment {M}ulti-{M}odal
                      {P}rofiling in {L}ong-{T}erm {R}esponders with {M}etastatic
                      {L}ung {C}ancer in the {N}ational {N}etwork {G}enomic
                      {M}edicine {L}ung {C}ancer {G}ermany (n{NGM}).},
      journal      = {Annals of oncology},
      volume       = {nn},
      issn         = {0923-7534},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2026-00026},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      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.},
      keywords     = {Lung cancer (Other) / discontinuation (Other) / immune
                      checkpoint blockade (Other) / long-term response (Other) /
                      resistance mechanisms (Other) / second primary lung cancer
                      (Other)},
      cin          = {A420 / BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)A420-20160331 / I:(DE-He78)BE01-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41478526},
      doi          = {10.1016/j.annonc.2025.12.011},
      url          = {https://inrepo02.dkfz.de/record/307521},
}