N2M2 (NOA-20) phase I/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma

Abstract

Background. Patients with glioblastoma without O 6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation are unlikely to benefit from alkylating chemotherapy with temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in unselected patient populations have failed to demonstrate any improvement of survival. Advances in molecular understanding and diagnostic precision enable identification of key genetic alterations in a timely manner and in principle allow treatments with targeted compounds based on molecular markers. Methods. The NCT Neuro Master Match (N 2 M 2) trial is an open-label, multicenter, phase I/IIa umbrella trial for patients with newly diagnosed isocitrate dehydrogenase (IDH) wildtype glioblastoma without MGMT promoter hypermethylation to show safety, feasibility, and preliminary efficacy of treatment with targeted compounds in addition to standard radiotherapy based on molecular characterization. N 2 M 2 is formally divided into a Discovery and a Treatment part. Discovery includes broad molecular neuropathological diagnostics to detect predefined biomarkers for targeted treatments. Molecular diagnostics and bioinformatic evaluation are performed within 4

Current usage of tumor treating fields for glioblastoma

“… 22 Similarly, the open-label multi-arm GBM-AGILE study (NCT03970447) also disallows TTF on all arms. The NOA-20 (N2M2) trial (NCT03158389, EudraCT 2015-002752-27) 23 also disallows TTF. Accrual does not suffer from this design, which to the contrary resulted mainly from concerns that mandating TTF usage would hinder the willingness of patients to participate, and if compliance differed between arms could create imbalance.…”

Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes

“…The effect of upfront alkylating agents vs targeted treatments in MGMT promoter unmethylated glioblastoma on its prognostic impact could be answered by subgroup analysis of our currently recruiting N 2 M 2 clinical study. 30 RTK I glioblastomas remain a less understood, poorly performing group that have lower DDR and overall methylation levels. Only MVP methylation was prognostic in this group, however, overall promoter methylation of this F I G U R E 4 DNA damage response (DDR) genes and therapy response in glioblastoma cells.…”

Autophagy as a Potential Therapy for Malignant Glioma

“…The results of the trial have not been published yet, but the frequency of adverse effects and the efficacy of each subtrial will be reported. The study will provide the basis to develop predictive biomarkers and select the best-suited treatment for each patient [415,416].…”