% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Cloughesy:305604,
      author       = {T. F. Cloughesy and M. J. van den Bent and M. Touat and D.
                      T. Blumenthal and K. B. Peters and B. M. Ellingson and J. L.
                      Clarke and J. Mendez and S. Yust-Katz and L. Welsh and W. P.
                      Mason and F. Ducray and Y. Umemura and B. Nabors and M.
                      Holdhoff and A. F. Hottinger and Y. Arakawa and J. M.
                      Sepulveda and W. Wick$^*$ and R. Soffietti and J. Perry and
                      P. Giglio and M. de la Fuente and E. Maher and A. Bottomley
                      and A. E. Tron and D. Yi and D. Zhao and S. S. Pandya and L.
                      Steelman and I. Hassan and P. Y. Wen and I. K. Mellinghoff},
      collaboration = {I. t. investigators},
      title        = {{V}orasidenib in {IDH}1-mutant or {IDH}2-mutant low-grade
                      glioma ({INDIGO}): secondary and exploratory endpoints from
                      a randomised, double-blind, placebo-controlled, phase 3
                      trial.},
      journal      = {The lancet / Oncology},
      volume       = {nn},
      issn         = {1470-2045},
      address      = {London},
      publisher    = {The Lancet Publ. Group},
      reportid     = {DKFZ-2025-02254},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {In a phase 3 trial, vorasidenib, an oral brain-penetrant
                      inhibitor of mutant isocitrate dehydrogenase 1 and 2
                      (IDH1/2), resulted in improved progression-free survival
                      (primary endpoint) and time to next intervention (key
                      secondary endpoint) at second interim analysis, resulting in
                      study unblinding. We report 6 months of additional
                      double-blind data, from second interim analysis (Sept 6,
                      2022) to unblinding (March 7, 2023), and the effect of
                      vorasidenib on volumetric tumour growth rate, health-related
                      quality of life (HRQOL), neurocognitive function, and
                      seizure control.INDIGO was a randomised, double-blind,
                      placebo-controlled, phase 3 trial done in 92 hospitals in
                      Canada, France, Germany, Israel, Italy, Japan, the
                      Netherlands, Spain, Switzerland, the UK, and the USA.
                      Patients aged 12 years or older with residual or recurrent
                      grade 2 IDH1/2-mutant diffuse glioma, a Karnofsky
                      performance-status score of 80 or higher, at least one
                      previous surgery, and no other previous anticancer treatment
                      were eligible. Patients were randomly assigned (1:1;
                      stratified according to locally determined chromosome 1p/19q
                      codeletion status and baseline tumour size) to oral
                      vorasidenib (40 mg) or placebo once a day in continuous
                      28-day cycles until disease progression or unacceptable
                      toxicity. Progression-free survival per masked independent
                      review committee was the primary endpoint, and time to next
                      intervention was the key secondary endpoint. Prespecified
                      secondary endpoints included tumour growth rate (6-monthly
                      change in tumour volume) and HRQOL (Functional Assessment of
                      Cancer Therapy-Brain [FACT-Br]). Prespecified exploratory
                      endpoints included neurocognitive function (cognitive
                      performance instruments) and seizure activity
                      (self-reported). The full analysis set was used for all
                      efficacy analyses and included all randomly assigned
                      patients, and the safety analysis set was used for all
                      safety analyses and included all patients who received one
                      or more doses of vorasidenib or placebo. The trial is
                      registered with ClinicalTrials.gov, NCT04164901. Recruitment
                      is complete and the trial is ongoing.Between Jan 9, 2020,
                      and Feb 22, 2022, 331 patients were enrolled and randomly
                      assigned to vorasidenib (n=168) or placebo (n=163). 187
                      $(56\%)$ patients were male, 144 $(44\%)$ were female, and
                      257 $(78\%)$ were White. Median follow-up was 20·1 months
                      (IQR 15·9 to 23·8). With an additional 6 months of
                      follow-up, median progression-free survival (not reached
                      $[95\%$ CI 22·1 to not estimated] vs 11·4 months $[95\%$
                      CI 11·1 to 13·9]; hazard ratio [HR] 0·35 $[95\%$ CI 0·25
                      to 0·49]) and time to next intervention (not estimated [not
                      estimated to not estimated] vs 20·1 months [17·5 to
                      27·1]; HR 0·25 [0·16 to 0·40]) remained substantially
                      improved with vorasidenib versus placebo. Tumour growth rate
                      was $-1·3\%$ $(95\%$ CI -3·2 to 0·7) with vorasidenib and
                      $14·4\%$ $(95\%$ CI 12·0 to 16·8) with placebo
                      (difference $15·9\%$ $[95\%$ CI 12·6 to 19·3]). Mean
                      FACT-Br total scores were similar between the vorasidenib
                      and placebo groups (158·2 [SD 26·4] and 158·8 [23·3]) at
                      baseline and remained high (154·2 [29·8] and 153·2
                      [29·4]) by the end of treatment. There was no difference
                      between vorasidenib or placebo in neurocognitive functions
                      of verbal learning, executive function, attention, working
                      memory, and psychomotor function from baseline through to
                      end of treatment. The vorasidenib group had lower rates of
                      seizures than the placebo group (18·2 seizures per
                      person-year $[95\%$ CI 8·4 to 39·5] vs 51·2 seizures per
                      person-year [22·9 to 114·8]). The most common grade 3 or
                      worse treatment-emergent adverse events (TEAEs) in the
                      vorasidenib and placebo groups, respectively, were increased
                      alanine aminotransferase (17 $[10\%]$ and two $[1\%]),$
                      increased aspartate aminotransferase (eight $[5\%]$ and
                      none), seizures (seven $[4\%]$ and five $[3\%]),$ and
                      increased γ-glutamyltransferase (five $[3\%]$ and two
                      $[1\%]).$ Serious TEAEs occurred in 20 $(12\%)$ patients in
                      the vorasidenib group and ten $(6\%)$ in the placebo group;
                      the most common were seizures. There were no
                      treatment-related deaths.Vorasidenib reduced tumour growth
                      rate and improved seizure control compared with placebo,
                      with no observed negative effects on HRQOL or
                      neurocognition. Additional follow-up supported the
                      robustness of progression-free survival and time to next
                      intervention in patients with grade 2 IDH1/2-mutant diffuse
                      glioma. These findings support the use of vorasidenib in
                      patients with grade 2 IDH1/2-mutant gliomas who only had
                      surgical intervention and are not in immediate need of
                      radiotherapy or chemotherapy.Servier.},
      cin          = {B320},
      ddc          = {610},
      cid          = {I:(DE-He78)B320-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41175888},
      doi          = {10.1016/S1470-2045(25)00472-3},
      url          = {https://inrepo02.dkfz.de/record/305604},
}