CTNI-85. FINAL RESULTS FROM N2M2/NOA-20

Abstract BACKGROUND MGMT promoter methylation determines benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Solid evaluation of the MGMT promotor methylation status is critical. METHODS The phase I/IIa umbrella trial NCT Neuro Master Match (N2M2) in patients with newly diagnosed glioblastoma aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to radiotherapy. In five subtrials (alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus) patients were included according to the best matching molecular alteration. Patients without matching alterations were randomized between atezolizumab, asunercept or TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). RESULTS From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. MGMT was determined locally and confirmed centrally by pyrosequencing as well as methylation arrays. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.8311) and a median overall survival (mOS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and mOS of 13.0 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and mOS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and mOS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and mOS of 15.4 months. For the other arms, phase IIa has not been reached. CONCLUSIONS There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients nor palbociclib in molecularly selected patients. Potential biomarkers will be discussed.