Background
CeTeG/NOA-09: Phase III, open-label, multicenter RCT. 141 patients with newly diagnosed glioblastoma with confirmed MGMT promoter methylation, age 18–70, KPS ≥70. The hypothesis was that more intensive alkylating chemotherapy with lomustine+temozolomide would improve OS in the molecularly selected MGMT-methylated population. Standard TMZ chemoradiotherapy was the comparator.
Interventions and follow up
Arm A: Standard temozolomide chemoradiotherapy — TMZ 75 mg/m²/day concurrent with 59–60 Gy RT, then 6 cycles TMZ 150–200 mg/m² days 1–5 every 28 day
Arm B: Lomustine + temozolomide — lomustine 100 mg/m² day 1 + TMZ 100–200 mg/m² days 2–6, up to 6 × 6-week cycles, with concurrent RT 59–60 Gy
Primary endpoint: Overall survival (modified ITT, N=129)
mFollow up: Not reported; final analysi
Arm B: Lomustine + temozolomide — lomustine 100 mg/m² day 1 + TMZ 100–200 mg/m² days 2–6, up to 6 × 6-week cycles, with concurrent RT 59–60 Gy
Primary endpoint: Overall survival (modified ITT, N=129)
mFollow up: Not reported; final analysi
Results
OS (mITT): 48.1 vs 31.4 months, HR 0.60 (95% CI 0.35–1.03), P=.0492
OS (ITT): HR 0.60, P=.0432
PFS: Not reported separately
OS (ITT): HR 0.60, P=.0432
PFS: Not reported separately
Adverse events
Main adverse events: Grade ≥3 AEs: 59% (lomustine+TMZ) vs 51% (TMZ alone). Hematologic toxicity significantly higher in lomustine+TMZ arm (thrombocytopenia, neutropenia). No treatment-related deaths. QoL and neurocognition (NOA-09 companion study) showed no clinically significant differences between arms despite survival benefit.
Conclusions
Lomustine+TMZ significantly improved OS vs standard TMZ in newly diagnosed MGMT-methylated GBM (48.1 vs 31.4 months; HR 0.60). The combination is now considered a treatment option for fit younger patients with MGMT-methylated GBM, though increased hematologic toxicity limits its use in older or frailer patients.
Key Limitations
Key Limitations: Small sample size (N=141, mITT=129) — the P value for the primary endpoint barely reached 0.05, and the confidence interval for HR crossed 1.0 (0.35–1.03), meaning the trial is underpowered for definitive conclusions. Different schedules (6-week vs 4-week cycles) make lomustine dosing complex and challenging to implement. Eligibility limited to MGMT-methylated patients — not applicable to unmethylated GBM. The lomustine+TMZ regimen is associated with significant hematologic toxicity. Open-label design.
Clinical Context
NOA-09 was the first phase III RCT to show superiority over the Stupp regimen in a molecularly selected GBM population. Despite underpowering concerns, the OS data (48.1 vs 31.4mo) are clinically striking. This regimen has been adopted in Germany and parts of Europe for MGMT-methylated GBM, and is included in ESMO and NCCN guidelines as an option for fit patients with MGMT-methylated GBM. Lomustine supply and hematologic monitoring add logistical challenges.
References
References: Herrlinger U et al, Lancet 2019 (NOA-09/CeTeG)