CATNON

Background

Phase III, open-label, 2×2 factorial RCT (EORTC 26053-22054, "CATNON"). 745 patients with newly diagnosed, non-1p/19q co-deleted anaplastic glioma (anaplastic astrocytoma or mixed glioma without 1p/19q codeletion). Tested 2 independent questions: (1) Does concurrent TMZ during RT improve outcomes? (2) Does adjuvant TMZ after RT improve outcomes? First large phase III trial exclusively in non-1p/19q codeleted anaplastic glioma — a group for whom the benefit of chemotherapy was unknown before this trial.

Interventions and follow up

Arm A: Radiotherapy alone (59.4 Gy/33fr)
Arm B: Radiotherapy + concurrent TMZ (75 mg/m²/day)
Arm C: Radiotherapy + adjuvant TMZ (12 cycles, 150–200 mg/m² days 1–5 q28d)
Arm D: Radiotherapy + concurrent TMZ + adjuvant TMZ
Primary endpoint: Overall survival
mFollow up: Interim analysis reported; final results updated in 2021

Results

Adjuvant TMZ effect (OS): HR 0.65 (95% CI 0.45–0.93), P=.002 — significant benefit
Concurrent TMZ effect: No significant OS benefit (HR ~1.0)
Median OS (adjuvant TMZ vs no): Not reached vs 41.1 months
IDH mutant (exploratory): Strong benefit from adjuvant TMZ; IDH wild-type patients had dismal outcomes regardless of treatment

Adverse events

Main adverse events: Grade 3–4 AEs higher in concurrent TMZ arms (hematologic). Adjuvant TMZ tolerability consistent with known profile. No unexpected late effects. Concurrent TMZ added toxicity without survival benefit.

Conclusions

Adjuvant TMZ (12 cycles after RT) significantly improved OS (HR 0.65) in non-1p/19q codeleted anaplastic glioma, establishing RT + adjuvant TMZ as standard of care for this population. Concurrent TMZ did not provide additional benefit — supporting that the adjuvant rather than concurrent component is the active contribution in this histotype.

Key Limitations

Key Limitations: The 2×2 factorial design requires the assumption of no interaction between concurrent and adjuvant TMZ — this may not hold. Interim analysis reported before full maturity. IDH molecular analysis was retrospective and unplanned at trial design. Non-1p/19q codeleted anaplastic glioma is now largely synonymous with IDH-mutant astrocytoma grade 3 (WHO 2021) — the IDH wild-type patients in this trial would now be classified as GBM. No direct comparison to PCV in this setting. 12 adjuvant cycles is more than standard 6 cycles.

Clinical Context

CATNON established RT + adjuvant TMZ as the standard of care for IDH-mutant astrocytoma grade 3 (previously non-1p/19q codeleted anaplastic glioma). The NCCN and ESMO recommend RT followed by adjuvant TMZ for grade 3 IDH-mutant astrocytoma. The benefit of concurrent TMZ in this population was not demonstrated, distinguishing the treatment approach from GBM where concurrent TMZ is essential. IDH mutation and 1p/19q codeletion testing are mandatory for all adult diffuse gliomas per WHO 2021.

References

References: van den Bent MJ et al, Lancet 2017 (CATNON)