Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a N2M2 umbrella trial

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 .

Fig. 1. The NCT N²M² trial CONSORT overview and concept.

a, Short CONSORT flow chart. EOS, end of study. b, Schematic overview of the trial. The trial was conducted in 13 centers in Germany and molecular tumor board-based allocation was performed into five match and three no-match arms, including one arm with SOC. PFS-6 estimation for SOC (40%) was based on an assumption before trial start and was later corrected to 23.1%. RT, radiotherapy; plus sign indicates that RT was always given in conjunction with one of the subsequently mentioned trial treatments. c, The diagnostic workup in the N²M² trial.

Fig. 2. Discovery—molecular assessments and trial arm allocation.

a–f, SOC (TMZ; a), arm A (asunercept; b), arm C (idasanutlin; c), arm D (atezolizumab; d), arm F (palbociclib; e) and arm G (temsirolimus; f) are shown. amp, amplified; del, deleted; mut, mutated; MES, mesenchymal.

Fig. 3. Primary endpoint phase 2a N²M².

Treatment—PFS-6 results of the N²M² trial.

Extended Data Fig. 1. CONSORT diagram.

Recruiting trial sites. In total, 301 patients were enrolled in 13 neurooncology working group (NOA) trial sites across Germany.

Extended Data Fig. 2. Trial sites.

Drawn map of Germany depicting the N²M² sites.

Extended Data Fig. 3. Survival results of subtrial A (asunercept) in the FAS.

a, Kaplan-Meier plot for PFS of subtrial A (n = 26) and SOC (n = 54). P-value shows result of log-rank test. b, Kaplan-Meier plot for OS of subtrial A (n = 26) and SOC (n = 54). P-value shows result of log-rank test.

Extended Data Fig. 4. Survival results of subtrial D (atezolizumab) in the FAS.

a, Kaplan-Meier plot for PFS of subtrial D (n = 42) and SOC (n = 54). P-value shows result of log-rank test. b, Kaplan-Meier plot for OS of subtrial D (n = 42) and SOC (n = 54). P-value shows result of log-rank test.

Extended Data Fig. 5. Survival results of subtrial F (palbociclib) in the FAS.

a, Kaplan-Meier plot for PFS of subtrial F (n = 41) and SOC (n = 54). P-value shows result of log-rank test. b, Kaplan-Meier plot for OS of subtrial F (n = 41) and SOC (n = 54). P-value shows result of log-rank test.

Extended Data Fig. 6. Survival results of subtrial G (temsirolimus) in the FAS.

a, Kaplan-Meier plot for PFS of subtrial G (n = 46) and SOC (n = 54). P-value shows result of log-rank test. b, Kaplan-Meier plot for OS of subtrial G (n = 46) and SOC (n = 54). P-value shows result of log-rank test.

Extended Data Fig. 7. Survival results for comparison of subtrial G (temsirolimus) to phospho-mTOR high patients in SOC.

a, Kaplan-Meier plot for PFS of subtrial G (n = 46) and phospho-mTOR high patients in SOC (n = 23). P-value shows result of log-rank test. b, Kaplan-Meier plot for OS of subtrial G (n = 46) and phospho-mTOR high patients in SOC (n = 23). P-value shows result of log-rank test.

Extended Data Fig. 8. Survival results for comparison of the three main methylation classes in treated patients.

a, Kaplan-Meier plot for PFS in patients with RTK1 (n = 58), RTK2 (n = 83) and MES (n = 66) tumors. b, Kaplan-Meier plot for OS in patients with RTK1 (n = 58), RTK2 (n = 83) and MES (n = 66) tumors.