RTOG 0525: A randomized phase iii trial comparing standard adjuvant temozolomide (tmz) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (gbm)

Radiotherapy with concomitant and adjuvant TMZ is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. This trial, conducted by the RTOG, EORTC, and NCCTG, determined if intensified TMZ improves survival (OS) or progression free survival (PFS) in all patients or specific to MGMT status. Eligibility criteria included age . 18 yrs, KPS ≥ 60, and existence of a tissue block with . 1cm2 tumor for prospective MGMT and retrospective molecular analysis. Patients were randomized to Arm 1: standard TMZ (150-200 mg/m2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m2 x 21 d) q 4 wks for 6-12 cycles. Symptom burden, quality of life (QOL), and neurocognition were prospectively and longitudinally assessed in a patient subset. 833 patients were randomized (1173 registered). Inadequate tissue (n ¼ 144) was the most frequent reason for nonrandomization.No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p ¼ 0.63), median PFS (5.5, 6.7 mo, p ¼ 0.06), or methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p , 0.0001), PFS (8.7, 5.7 mo, p , 0.0001), and treatment response (p ¼ 0.012). Cox modeling identifiedMGMT status and RPA class as significant predictors of OS; treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade ≥ 3 toxicity in Arm 2 (19%, 27%, p ¼ 0.008), which was mostly lymphopenia and fatigue. This study did not demonstrate improved efficacy for dd TMZ for newly diagnosed GBM regardless of methylation status. However, it confirmed the prognostic significance of MGMT methylation in GBM, demonstrated the feasibility of tumor tissue collection, molecular stratification, and collection of patient outcomes in a large transatlantic intergroup trial, thereby establishing a viable clinical trial paradigm. Support: NCI U10 CA 21661 and U10 CA37422

Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG.

Radiation with concurrent and adjuvant (6 cycles) temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial. We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMT methylation. A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio [HR] 0.80 [0.65-0.98], P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 [0.50-0.85], P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 [0.71-1.19], P = .52), including the MGMT methylated subgroup (HR = 0.89 [0.63-1.26], P = .51). Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM

Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, IDH-wildtype: Post Hoc Analysis of the EORTC Randomized Phase III CATNON Trial

Purpose: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblas-toma [redesignated as glioblastoma, isocitrate dehydrogenase- wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors].Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and con-current temozolomide to radiotherapy in anaplastic astrocyto-mas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis.Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82-1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61-1.24). MGMT promoter methyl-ation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival.Conclusions: In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany

Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma

Background. Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients.Methods. The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization.Results. Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication.Conclusion. Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification

Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study

BACKGROUND: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. METHODS: This was a phase 3, randomised, open-label study with a 2 x 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59.4 Gy in 33 fractions of 1.8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m(2) temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m(2) per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0.0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. FINDINGS: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0.65 (99.145% CI 0.45-0.93). Overall survival at 5 years was 55.9% (95% CI 47.2-63.8) with and 44.1% (36.3-51.6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. INTERPRETATION: Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. FUNDING: Schering Plough and MSD