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

Wolfgang Wick ¹, Lisa-Marie Lanz ², Antje Wick ³, Inga Harting ⁴, Susan Dettmer ², Abigail K Suwala ⁵, Ralf Ketter ⁶, Ghazaleh Tabatabai ^7 8, Corinna Seliger ^3 9, Martin Glas ¹⁰, Michael C Burger ¹¹, Marco Timmer ¹², Florian A Ringel ^13 14, Iris Mildenberger ^15 16, Walter J Schulz-Schaeffer ¹⁷, Frank Winkler ³, Laila König ¹⁸, Christel Herold-Mende ¹⁹, Andreas Eisenmenger ², Stefan M Pfister ²⁰, Mirjam Renovanz ^7 8 21, Martin Bendszus ⁴, Felix Sahm ²², Michael Platten ^15 16, Tobias Kessler ³

Affiliations Expand

·         PMID: 40913172

·         PMCID: PMC12532562

·         DOI: 10.1038/s41591-025-03928-9

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 .

Abstract

• 배경: GBM의 분자적 이해와 진단 정확도가 향상되면서 주요 유전적 변이를 확인하고, 분자표지자에 맞는 표적치료제를 선택하는 것이 가능해짐.

• 연구목적: MGMT promoter 과메틸화가 없는 새로 진단된 GBM 환자 228명을 대상으로, 종양의 분자적 특성에 맞는 표적치료제 + 방사선치료의 효과를 평가함.

• 연구설계: 1/2상 N2M2 우산형 임상시험. Molecular tumor board가 환자의 분자적 변이에 가장 적합한 치료제를 선택함.

  • Alectinib

  • Idasanutlin

  • Palbociclib

  • Vismodegib

  • Temsirolimus

  • 일치하는 분자적 변이가 없는 환자 → Atezolizumab, Asunercept 또는 SOC(temozolomide)

• 치료: 모든 환자에게 방사선치료 시행.

• 주요 평가변수: 

  • 1상 → 용량제한독성(DLT)

  • 2상 → 6개월 무진행생존율(PFS-6) 

• 결과: 

  • Alectinib, Vismodegib → 일치하는 환자가 없어 시험 미개시

  • Idasanutlin → 9명 등록 후 제조사 결정으로 조기 종료

  • Temsirolimus(n=46) → mTOR signaling 활성화 환자에서 PFS-6 39.1%, median OS 15.4개월

  • SOC군(n=54) → PFS-6 18.5% 

  • Temsirolimus군은 주요 평가변수 충족 

  • Atezolizumab, Asunercept, Palbociclib → 유효성에 대한 주요 평가변수 미충족 

• 안전성: N2M2에서 나타난 안전성은 기존 해당 약물의 경험과 유사했으며, 방사선치료와의 유의한 부정적 상호작용은 관찰되지 않음. 

• 결론: mTOR signaling이 활성화된 새로 진단된 GBM 환자에서 방사선치료에 temsirolimus를 추가하는 치료전략을 추가적으로 연구할 근거를 제시함.

Fig. 3. Primary endpoint phase 2a N²M²