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Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24–78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours. Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma. • Data on 280 patients with glioblastoma, among them 189 with IDH wildtype tumours, are reported. • In total, 139 of 189 patients (74.3%) had tumours with MGMT promoter methylation. • Median overall survival was 9.9 years (95% CI 7.9–11.9). • Patients without recurrence had longer survival than patients with one or more recurrences. [ABSTRACT FROM AUTHOR]

Background: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear., Methods: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m 2 per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m 2 temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990., Findings: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported., Interpretation: 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., Funding: Merck Sharpe & Dohme., Competing Interests: Declaration of interests MJvdB reports grants from the Dutch Cancer Foundation, Brain Tumor Charity, Strijd van Salland, and Merck Sharp & Dohme (formerly Schering Plough), during the conduct of the study; and personal fees from Carthera, Nerviano, Bayer, Cellgene, Agios, AbbVie, Karyopharm, Boston Pharmaceuticals, and Genenta, outside the submitted work. PMC reports personal fees from Bristol Meyers Squibb, AbbVie, Merck Serono, Merck Sharp & Dohme, Vifor Pharma, DaNchi Sankyo, LEO Pharma, AstraZeneca, and Takeda, outside the submitted work. MAV reports grants from the US National Cancer Institute, during the conduct of the study, and personal fees from Tocagen and Celgene, outside the submitted work. AKN reports grants and personal fees from AstraZeneca, and Douglas Pharmaceuticals, and personal fees from Bayer Pharmaceuticals, Roche Pharmaceuticals, Boehringer Ingelheim, Merck Sharp & Dohme, Pharmabcine, Atara Biotherapeutics, and Trizell, outside the submitted work. MW reports grants and personal fees from AbbVie, Merck Sharp & Dohme, Merck (EMD); grants from Adastra, Novocure; and personal fees from Basilea, Bristol Myer Squibbs, Celgene, Nerviano, Orbus, Roche, and Tocagen, outside the submitted work. UH reports non-financial support from Medac, and personal fees from Novartis, Daiichi-Sankyo, Noxxon, AbbVie, Bayer, Janssen, and Karyopharm, outside the submitted work. HJD reports personal fees from AbbVie, outside the submitted work. BGB reports personal fees and non-financial support from Roche, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)