Second interim and first molecular analysis of the EORTC randomized phase III intergroup CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q codeletion.

Abstract

2000 Background: The 1st interim analysis of the CATNON trial showed benefit from adjuvant (adj) temozolomide (TMZ) on overall survival (OS) but remained inconclusive about concurrent (conc) TMZ. A 2nd interim analysis was planned after 356 events. Methods: The 2x2 factorial design phase III CATNON trial randomized 751 adult patients with newly diagnosed non-codeleted anaplastic glioma to either 59.4 Gy radiotherapy (RT) alone; the same RT with concTMZ; the same RT and 12 cycles of adjTMZ or the same RT with both concTMZ and adjTMZ ( doi: 10.1016/S0140-6736(17)31442-3). MGMT promoter methylation ( MGMTmeth) status was re-assessed with the Infinium Methylation EPIC Beadchip using the MGMT_STP27 model. Isocitrate dehydrogenase 1 and 2 ( IDH) mutation (mt) status was assessed with glioma targeted Agilent SureSelect baits sequence using an Illumina HiSeq2500 Rapid PE100. Results: With a median follow-up of 56 months and 356 events, the hazard ratio (HR) for OS adjusted for stratification factors after concTMZ was 0.968 (99.1% CI 0.73, 1.28). 5-year OS was 50.2% with and 52.7% without concTMZ (95% CI [44.4, 55.7] and [46.9, 58.1]). An IDHmt was found in 335 of 480 assessed cases (70%). Median OS was 19 mo (95% CI 16.3, 22.3) in IDHwt tumors and 116 mo (95% CI 82.0, 116.6) in IDHmt tumors. HR for OS after concTMZ in patients with known IDH status. Clinical trial information: NCT00626990. IDHmt was predictive of benefit from adjTMZ ( IDHmt HR: 0.41, 95% CI 0.27, 0.64; IDHwt: HR 1.05, 95% CI 0.73, 1.52; interaction test p = 0.001). In IDHmt patients that received adjTMZ, the HR for OS after concTMZ was 0.71 (95% CI 0.35, 1.42, p=0.32). MGMTmeth was found in 288 of 410 assessed cases (70%), interaction test for concTMZ (p = 0.092) and adjTMZ (p = 0.166) did not reach statistical significance. Conclusions: In the entire study cohort, concTMZ did not increase OS. However, in IDHmt tumors a trend towards benefit of concTMZ is present. AdjTMZ increased OS in IDHmt but not in IDHwt tumors. The ongoing molecular analyses and further follow-up will allow full assessment of efficacy in the molecular subgroups.[Table: see text]