In the second interim analysis of the phase III CATNON trial reported in The Lancet Oncology, Martin J. van den Bent, MD, PhD, and colleagues found that adjuvant temozolomide—but not temozolomide concurrent with radiotherapy—was associated with an overall survival benefit in patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma. Benefit was driven by outcomes in patients with IDH1/IDH2 mutation.   

Martin J. van den Bent, MD, PhD

Study Details

In the open-label trial, 751 patients with newly diagnosed disease from sites in Australia, Europe, and North America were randomly assigned 1:1:1:1 between December 2007 and September 2015 to receive: 

• Radiotherapy alone (n = 189; 59.4 Gy in 33 fractions with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy)
• Radiotherapy with concurrent temozolomide at 75 mg/m² per day (n = 188)
• Radiotherapy with adjuvant temozolomide given in 12 4-week cycles of 150 to 200 mg/m² on days 1 through 5 (n = 186)
• Radiotherapy with both concurrent and adjuvant temozolomide (n = 188).

The primary endpoint was overall survival in the intention-to-treat population.

Overall Survival

Median follow-up was 55.7 months (interquartile range = 41.0–77.3 months). Futility of concurrent temozolomide vs no concurrent temozolomide was declared: median overall survival was 66.9 months (95% confidence interval [CI] = 45.7–82.3 months) with concurrent temozolomide vs 60.4 months (95% CI = 45.7–71.5 months) without concurrent temozolomide (hazard ratio [HR] = 0.97, 99.1% CI = 0.73–1.28, P = .76). Adjuvant temozolomide improved overall survival vs no adjuvant temozolomide: median overall survival was 82.3 months (95% CI = 67.2–116.6 months) with adjuvant temozolomide vs 46.9 months (95% CI =37.9–56.9 months) with no adjuvant temozolomide (HR = 0.64, 95% CI = 0.52–0.79, P < .0001).

Among all patients, median overall survival was 19.9 months (95% CI = 16.8–22.7 months) among patients with IDH1 and IDH2 wild-type tumors vs 98.4 months (95% CI = 85.2–116.6 months) among those with IDH1- or IDH2-mutant tumors (approximately 60% of population; HR = 0.14, 95% CI = 0.12–0.18, P < .0001). Among patients with IDH1 and IDH2 wild-type tumors, neither concurrent nor adjuvant temozolomide improved overall survival vs radiotherapy alone. Among patients with IDH1- or IDH2-mutant tumors, adjuvant temozolomide improved overall survival vs no adjuvant temozolomide, but no benefit was observed for concurrent temozolomide vs no concurrent temozolomide. Tests for interaction showed that IDH1 and IDH2 mutation status was highly significant for benefit of adjuvant temozolomide (P = .001), but not for concurrent temozolomide (P = .29).

Toxicity

Nonhematologic grade 3 and 4 adverse events were rare. Grade 3 and 4 hematologic adverse events (none in the radiotherapy-only group) occurred in 15% of the combined adjuvant temozolomide groups and 9% of the concurrent temozolomide group, including thrombocytopenia in 10% vs 8% and neutropenia in 7% vs 3%. Treatment was discontinued due to adverse events in 4% of patients receiving concurrent temozolomide, 8% of patients receiving adjuvant temozolomide, and 15% of patients receiving concurrent and adjuvant temozolomide. No treatment-related deaths were reported.

The investigators concluded, “Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non–co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.”

Dr. van den Bent, of the Brain Tumor Center at Erasmus MC Cancer Institute, Rotterdam, is the corresponding author for The Lancet Oncology article.  

Disclosure: The study was funded by Merck Sharpe & Dohme. For full disclosures of the study authors, visit thelancet.com.