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@ARTICLE{Wick:304464,
      author       = {W. Wick$^*$ and L.-M. Lanz$^*$ and A. Wick$^*$ and I.
                      Harting and S. Dettmer$^*$ and A. K. Suwala$^*$ and R.
                      Ketter and G. Tabatabai and C. Seliger and M. Glas and M. C.
                      Burger and M. Timmer and F. A. Ringel and I.
                      Mildenberger$^*$ and W. J. Schulz-Schaeffer and F.
                      Winkler$^*$ and L. König and C. Herold-Mende and A.
                      Eisenmenger$^*$ and S. Pfister$^*$ and M. Renovanz and M.
                      Bendszus and F. Sahm$^*$ and M. Platten$^*$ and T.
                      Kessler$^*$},
      title        = {{M}olecularly matched targeted therapies plus radiotherapy
                      in glioblastoma: the phase 1/2a {N}2{M}2 umbrella trial.},
      journal      = {Nature medicine},
      volume       = {nn},
      issn         = {1078-8956},
      address      = {[New York, NY]},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2025-01857},
      pages        = {nn},
      year         = {2025},
      note         = {#EA:B320#LA:B320# / epub},
      abstract     = {Advances in molecular understanding and diagnostic
                      precision of glioblastoma enable the identification of key
                      genetic alterations in a timely manner and, in principle,
                      allow treatments with targeted compounds based on molecular
                      markers. Here we report the results of the phase 1/2
                      umbrella trial NCT Neuro Master Match (N2M2), which
                      evaluated targeted treatments in 228 patients with newly
                      diagnosed glioblastoma without O6-methylguanine
                      DNA-methyltransferase promoter hypermethylation.
                      Stratification for treatment was conducted by a
                      trial-specific molecular tumor board across five subtrials,
                      each evaluating a targeted therapy-alectinib, idasanutlin,
                      palbociclib, vismodegib or temsirolimus-selected according
                      to the best-matching molecular alteration. Patients without
                      matching alterations were randomized between subtrials
                      without strong biomarkers using atezolizumab and asunercept,
                      and the standard of care (SOC), temozolomide. All received
                      radiotherapy. The primary endpoints were dose-limiting
                      toxicities (phase 1) and progression-free survival at 6
                      months (PFS-6; phase 2). Secondary endpoints included safety
                      and tolerability, as well as overall survival (OS). The
                      subtrials for alectinib and vismodegib did not open as they
                      did not have matching patients. The idasanutlin subtrial (n
                      = 9) was terminated early at the discretion of the
                      manufacturing company. The temsirolimus subtrial (n = 46)
                      demonstrated a PFS-6 of $39.1\%$ and median OS of 15.4
                      months in patients with activated mammalian target of
                      rapamycin (mTOR) signaling compared to a PFS-6 at $18.5\%$
                      in the SOC group (n = 54), meeting the primary endpoint. The
                      atezolizumab (n = 42), asunercept (n = 26) and palbociclib
                      (n = 41) subtrials did not meet the primary endpoint for
                      efficacy. The safety signals of N2M2 match prior experiences
                      with the drugs in quality and quantity; no relevant negative
                      interaction with the parallel radiotherapy was noted. The
                      results of the N2M2 trial support further investigation of
                      temsirolimus in addition to radiotherapy in patients with
                      newly diagnosed glioblastoma with activated mTOR signaling.
                      ClinicalTrials.gov registration: NCT03158389 .},
      cin          = {B320 / HD01 / W010 / B300 / D170 / B062},
      ddc          = {610},
      cid          = {I:(DE-He78)B320-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)W010-20160331 / I:(DE-He78)B300-20160331 /
                      I:(DE-He78)D170-20160331 / I:(DE-He78)B062-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40913172},
      doi          = {10.1038/s41591-025-03928-9},
      url          = {https://inrepo02.dkfz.de/record/304464},
}