CATNON
Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study
Year of Publication: 2021
Authors: van den Bent MJ, Tesileanu CMS, Wick W, ..., Clement PM
Journal: Lancet Oncology
Citation: Lancet Oncology 2021;22(6):813-823
Link: https://doi.org/10.1016/S1470-2045(21)00090-5
PDF: https://www.thelancet.com/action/showPdf...2045(21)00090-5
PDF: Clinical Question
Does concurrent temozolomide, adjuvant temozolomide, or both added to radiotherapy improve overall survival in 1p/19q non-co-deleted anaplastic glioma, and does IDH mutation status modify the effect?
Bottom Line
Adjuvant temozolomide added to radiotherapy significantly improved overall survival (median 82.3 vs 46.9 months; HR 0.64, p<0.0001) in 1p/19q non-co-deleted anaplastic glioma, while concurrent temozolomide did NOT add benefit (HR 0.97, p=0.76). Clinical benefit was strongly dependent on IDH mutational status — establishing adjuvant TMZ as the standard of care for IDH-mutant disease.
Major Points
- Phase 3, multicenter, open-label, 2×2 factorial randomized trial
- 137 institutions in Australia, Europe, and North America
- 751 adults with newly diagnosed 1p/19q non-co-deleted anaplastic glioma (WHO PS 0-2), randomly assigned 1:1:1:1
- RT: 59.4 Gy in 33 fractions (3D conformal or IMRT)
- Concurrent TMZ: 75 mg/m²/d during RT
- Adjuvant TMZ: 12 cycles of 150-200 mg/m² on days 1-5 of 28-day cycles
- Both arms: concurrent during RT + 12 adjuvant cycles
- Stratified by institution, WHO PS, age, 1p LOH, oligodendroglial elements, and MGMT methylation status
- Primary endpoint: overall survival adjusted by stratification factors (ITT)
- Second interim analysis (Dec 2019) triggered when 2/3 of required events observed
- Median follow-up 55.7 months (IQR 41.0-77.3)
- Concurrent TMZ: FUTILITY declared — median OS 66.9 vs 60.4 months; HR 0.97 (99.1% CI 0.73-1.28); p=0.76
- Adjuvant TMZ: SIGNIFICANT benefit — median OS 82.3 vs 46.9 months; HR 0.64 (95% CI 0.52-0.79); p<0.0001
- Grade 3-4 hematologic toxicities: 0% RT-alone, 9% concurrent, 15% adjuvant (or both arms combined)
- No treatment-related deaths reported
- Key finding: clinical benefit depended on IDH1/IDH2 mutational status — IDH-mutant patients benefit most; IDH-wildtype outcomes distinct
- This analysis changed practice: adjuvant TMZ is the cornerstone; concurrent TMZ has no added benefit in this molecular subtype
- Final definitive 2023/2024 publications refined IDH subgroup recommendations
Design
Study Type: Phase 3, multicenter, open-label, randomized, 2×2 factorial design
Randomization: 1
Blinding: Open-label
Enrollment Period: December 2007 - September 2015
Follow-up Duration: Median 55.7 months at second interim analysis
Centers: 137
Countries: Australia, Europe (multiple), USA, Canada
Sample Size: 751
Analyzed: 751
Analysis: Intention-to-treat; stratified Cox proportional hazards adjusted for stratification factors
Registration: NCT00626990
Inclusion Criteria
- Age ≥18 years
- Newly diagnosed anaplastic glioma
- 1p/19q non-co-deleted (locally or centrally determined)
- WHO performance status 0-2
- Adequate organ function
Exclusion Criteria
- 1p/19q codeleted tumors (received PCV regimen instead)
- Prior cranial radiotherapy or chemotherapy
- Other WHO grade of glioma
- Poor performance status
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| N | 189 | 562 |
| Arm | RT alone | |
| Age distribution | Typical for anaplastic glioma, median ~50s | |
| IDH mutant proportion | Substantial minority | |
| MGMT methylated | Proportion similar across arms | |
| Arms | RT + concurrent (188); RT + adjuvant (186); RT + both (188) | |
| Balanced | Stratification factors balanced |
Arms
| Field | Control | RT + concurrent TMZ | RT + adjuvant TMZ | RT + concurrent + adjuvant TMZ |
|---|---|---|---|---|
| N | 189 | 188 | 186 | 188 |
| Intervention | 59.4 Gy in 33 fractions (3D-CRT or IMRT) | RT + TMZ 75 mg/m²/d during RT | RT + 12 cycles adjuvant TMZ 150-200 mg/m² days 1-5 of 28-day cycle | RT + concurrent TMZ + 12 adjuvant cycles |
| Duration | 6 weeks RT | 6 weeks | ~1 year | ~1 year |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Overall survival, adjusted for stratification factors (ITT) | Primary | No adjuvant TMZ: median OS 46.9 mo (37.9-56.9) | Adjuvant TMZ: median OS 82.3 mo (67.2-116.6) | Adjuvant TMZ HR 0.64 (95% CI 0.52-0.79); concurrent TMZ HR 0.97 (99.1% CI 0.73-1.28) | p<0.0001 for adjuvant TMZ; p=0.76 for concurrent TMZ (futility) |
| Overall survival — concurrent TMZ vs no concurrent TMZ | Secondary | 60.4 mo (45.7-71.5) | 66.9 mo (45.7-82.3) | HR 0.97 (99.1% CI 0.73-1.28) | p=0.76 (FUTILITY declared) |
| Overall survival — adjuvant TMZ vs no adjuvant TMZ | Secondary | 46.9 mo (37.9-56.9) | 82.3 mo (67.2-116.6) | HR 0.64 (95% CI 0.52-0.79) | p<0.0001 |
| Benefit of adjuvant TMZ by IDH status | Secondary | IDH-wildtype: limited benefit | IDH-mutant: durable substantial benefit | Effect modified by IDH status | |
| Progression-free survival | Secondary | Shorter with RT alone | Longer with adjuvant TMZ arms | Consistent with OS direction | Favorable for adjuvant |
| Grade 3-4 hematologic toxicity — RT alone | Adverse | 0/185 (0%) | N/A | Baseline reference | |
| Grade 3-4 hematologic toxicity — concurrent TMZ arm | Adverse | 0% | 16/185 (9%) | Expected with TMZ | |
| Grade 3-4 hematologic toxicity — any adjuvant TMZ arm | Adverse | 0% | 55/368 (15%) | Cumulative with prolonged adjuvant | |
| Severe infections | Adverse | Uncommon | Rare | No safety signal | |
| Treatment-related deaths | Adverse | None | None | No fatal toxicity | |
| Discontinuation due to AEs | Adverse | Low | Low-moderate | Tolerable regimen |
Subgroup Analysis
Effect of adjuvant temozolomide on OS was strongly dependent on IDH1/IDH2 mutational status: IDH-mutant tumors derived substantial and durable benefit; IDH-wildtype tumors had a different (often poorer) baseline prognosis and modified benefit pattern. The molecular stratification reshaped classification of anaplastic gliomas (now termed astrocytoma/oligodendroglioma per WHO 2021) and the role of temozolomide within each molecular subtype.
Criticisms
- Open-label design may affect time-to-event assessments
- Second interim analysis for concurrent TMZ declared futility on a prespecified boundary
- Long enrollment period (2007-2015) introduces evolving imaging and pathology standards
- IDH mutation status not required at enrollment (available retrospectively in most patients)
- Standard 59.4 Gy dose and fractionation may differ from current practice in some centers
- Results are specific to non-codeleted tumors; do NOT extend to 1p/19q codeleted anaplastic oligodendroglioma (use PCV per EORTC 26951/RTOG 9402)
Funding
Merck Sharp & Dohme (MSD); government grants; CAN Foundation
Based on: CATNON (Lancet Oncology, 2021)
Authors: van den Bent MJ, Tesileanu CMS, Wick W, ..., Clement PM
Citation: Lancet Oncology 2021;22(6):813-823
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