GLARIUS Trial Research Articles

The proneural subtype is not associated with survival benefit from bevacizumab in newly diagnosed glioblastoma: a secondary analysis of the GLARIUS trial

PurposeThe AVAglio trial reported a significant survival benefit for first line bevacizumab treatment in patients with IDH wildtype glioblastoma of the proneural gene expression subtype. We here aim to replicate these findings in an independent trial cohort.MethodsWe evaluate the treatment benefit of bevacizumab according to gene expression subtypes of pretreatment tumor samples (n = 123) in the GLARIUS trial (NCT00967330) for MGMT unmethylated glioblastoma patients with Kaplan-Meier analyses, log-rank tests and Cox regression models.ResultsEmploying the Phillips classifier, bevacizumab conferred a significant PFS advantage in patients with proneural IDH wild-type tumors (10.4 vs. 6.0 months, p = 0.002), but no OS advantage (16.4 vs. 17.4 months, p = 0.6). Multivariable analysis adjusting for prognostic covariates confirmed the absence of a significant OS advantage from bevacizumab (hazard ratio, 1.05, 95% CI, 0.42 to 2.64; p = 0.14). Further, there was no interaction between the proneural subtype and treatment arm (p = 0.15). These results were confirmed in analyses of tumor subgroups according to the Verhaak classifier.ConclusionIn contrast to AVAglio, glioblastoma gene expression subgroups were not associated with a differential OS benefit from first-line bevacizumab in the GLARIUS trial.

Tumor growth patterns of MGMT-non-methylated glioblastoma in the randomized GLARIUS trial

We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. In 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher's exact test. At baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant difference in the fraction of tumors that changed from an initially local tumor growth pattern to a multifocal pattern (12 and 13%, p = 0.55). Distant lesions appeared in 17% (BEV/IRI) and 13% (TMZ) of patients (p = 0.69). 15% of patients in the BEV/IRI arm and 8% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.42). The tumor growth and invasiveness patterns do not differ between BEV/IRI and TMZ-treated MGMT-non-methylated glioblastoma patients in the GLARIUS trial. BEV/IRI was not associated with an increased rate of multifocal, distant, or highly invasive tumors at the time of recurrence.

SURG-01. COMPLETE RESECTION IS NOT ASSOCIATED WITH IMPROVED SURVIVAL IN MGMT NON-METHYLATED GLIOBLASTOMA: RESULTS FROM THE GLARIUS TRIAL

Abstract Background: Although it is known that upfront complete surgical resection is associated with improved survival in glioblastoma, studies are lacking to confirm whether this holds true for the unfavorable patient population of O-6-methylguanine-DNA methyltransferase (MGMT) non-methylated glioblastoma. Here, we investigated the association of survival with the extent of resection in the GLARIUS study, a randomized phase II trial of bevacizumab/irinotecan (BEV/IRI) versus standard temozolomide (TMZ) in MGMT non-methylated glioblastoma. Methods: Patients included in the modified intention-to-treat (ITT, n=170) population were stratified by extent of resection (partial vs. complete) as determined by early (>72h) postoperative contrast-enhanced MRI. In a Kaplan-Meier analysis, we compared overall survival (OS) between the groups in each treatment arm. A Cox regression analysis was used to detect whether complete resection was of prognostic value and independent of canonical prognostic markers, including age and Karnofsky performance score (KPS). Results: In the BEV/IRI arm, 58 patients (50%) each underwent partial (PR) and complete resection (CR). In the TMZ arm, 29 patients (55%) underwent partial and 24 (45%) complete resection. Prognostic factors, including age and KPS, were balanced between patients with PR and CR. Neither in the BEV/IRI arm (CR, median OS [mOS], 17.3 [95% CI, 15.5-21.4] versus PR, mOS, 16.5 [95% CI, 14.9-17.9]; Hazard Ratio [HR], 0.79 [95% CI, 0.53-1.20]; p=0.28) nor in the TMZ arm (CR, mOS, 18.0 [95% CI, 17.1-21.3] versus PR, mOS, 15.3 [95% CI, 10.6-21.1]; HR, 0.77 [95% CI, 0.43-1.40]; p=0.40) patients with CR derived a significant OS benefit compared to those with PR. In a multivariable Cox regression analysis, this effect did not change after accounting for canonical prognostic markers. Conclusions: In the GLARIUS trial, patients with complete resection derived no relevant survival benefit as compared with partially resected patients. However, the small sample size, in the TMZ arm in particular, limits our analysis.

P16.11 Complete resection is not associated with improved survival in MGMT non-methylated glioblastoma. Results from the GLARIUS trial

P16.11 Complete resection is not associated with improved survival in MGMT non-methylated glioblastoma. Results from the GLARIUS trial

P09.20 Effect of age on outcome in the GLARIUS trial

P09.20 Effect of age on outcome in the GLARIUS trial

NIMG-40MRI TUMOR PROGRESSION PATTERNS IN THE GLARIUS TRIAL

BACKGROUND: We evaluated patterns of tumor progression in patients with primary glioblastoma who were assigned to undergo treatment with bevacizumab/irinotecan (BEV/IRI) versus standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. METHODS: In 160 patients (106 BEV/IRI, 54 TMZ), we reviewed magnetic resonance imaging (MRI) scans at baseline and tumor progression. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) images we assessed tumor patterns and invasiveness. Tumor patterns were classified as either multifocal or local at baseline and progression; at progression, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations were calculated using Fisher's exact test. RESULTS: At baseline, 118 of 160 evaluable patients (73.8%) had a locally confined tumor. In the BEV/IRI arm 10% and in the TMZ arm 8% of patients with an initially local tumor growth changed to a multifocal pattern (p = 0.78); distant lesions were found in 24% in the BEV/IRI arm and 19% in the TMZ arm (p = 0.55). 8% of patients in the BEV/IRI arm and 11% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.58). CONCLUSIONS: The tumor progression and invasiveness patterns do not differ between BEV/IRI and TMZ-treated patients in the GLARIUS trial. BEV/IRI did not increase the rate of multifocal, distant or highly invasive tumors at the time of progression.

NIMG-41MRI FINDINGS IN THE GLARIUS TRIAL: PROGNOSTIC AND PREDICTIVE IMPLICATIONS

BACKGROUND: The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-DNA methyltransferase (MGMT) non-methylated glioblastoma to experimental bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ). BEV/IRI prolonged progression-free survival but overall survival (OS) was similar in both arms. To identify subpopulations with a particularly favourable course, we assessed the prognostic potential of magnetic resonance imaging (MRI) markers at baseline and during the first 4 months of treatment. METHODS: MRIs at baseline, 8, and 16 weeks after therapy initiation were analyzed for T1-hyperintense and diffusion-restricted lesions, contrast-enhancing lesions qualifying for tumor progression (25% increase), and progression of Fluid-attenuated inversion recovery (FLAIR) hyperintense lesions. The MRI findings were correlated with survival. RESULTS: None of the baseline parameters was prognostic in the entire cohort or predictive in the BEV/IRI arm. The presence of diffusion-restricted lesions was neither prognostic nor predictive of BEV/IRI benefit at any timepoint. At 8 weeks of follow-up, 49 patients developing a new combined diffusion-restricted and T1-hyperintense lesion had significantly greater OS than 90 patients without such changes (median OS, 17.5 vs. 15.7 months, p = 0.003). This effect was significant in the BEV/IRI arm (median OS, 17.2 vs. 15.7 months, p = 0.026) whereas significance was narrowly missed in the TMZ arm (median, 18.0 vs. 14.8 months, p = 0.071). At 16 weeks, OS in BEV/IRI-treated patients experiencing exclusively progressive FLAIR hyperintensities (17 of 52 evaluable patients; median OS, 17.5 months) was no worse than in BEV/IRI-treated patients with no progression on FLAIR and T1-weighted contrast-enhancing images (median OS, 19.4 months). In contrast, patients with progressive contrast-enhancing lesions had significantly shorter OS (median, 14.3 months, p = 0.0003, logrank test). CONCLUSIONS: The development of combined T1-hyperintense and diffusion-restricted lesions in early follow-up MRIs is associated with improved OS, particularly in BEV/IRI-treated patients. FLAIR-only progression does not appear to be predictive of a worse outcome with BEV/IRI treatment.

QL-13 * QUALITY OF LIFE AND COGNITIVE FUNCTIONING IN THE RANDOMIZED, MULTICENTER GLARIUS TRIAL INVESTIGATING BEVACIZUMAB/IRINOTECAN VS STANDARD TEMOZOLOMIDE IN NEWLY DIAGNOSED, MGMT-NON-METHYLATED GLIOBLASTOMA PATIENTS

BACKGROUND: In the GLARIUS trial, progression-free survival was significantly prolonged and overall survival was similar in both arms. The present report focuses on quality of life (QoL), Karnofsky performance score (KPS) and cognitive functioning during first-line and postprogression therapy. METHODS: Patients (n = 170) with newly diagnosed, MGMT-non-methylated glioblastoma were randomized 2:1 for bevacizumab (BEV)/irinotecan (IRI) therapy or standard temozolomide (TMZ) therapy. Every 3 months, KPS, QoL (EORTC-QLQ C30 and BN20) and cognitive functioning (MMSE) was determined. Analysis included a longitudinal mixed model analysis and a Kaplan-Meier analysis of the time to deterioration (10 points in QoL, points, 3 points in MMSE, 20% in KPS; tumor progression not regarded as an event). RESULTS: In KPS, MMSE and all 5 prespecified dimensions of QoL (global health status, physical functioning, social functioning, motor dysfunction, communication deficit) mixed model analyses and time to first deterioration analyses did not detect differences between the treatment arms. Time to deterioration of nausea/vomiting was shorter with BEV/IRI (p = 0.024). At progression, the crossover rate in the BEV/IRI arm (to TMZ) and in the standard TMZ arm (to BEV/(IRI) was identical with 65%. Time to postprogression deterioration was significantly longer in the standard TMZ arm receiving crossover BEV/(IRI) in the majority of patients regarding 13 of 26 QoL dimensions including prespecified global health status, social functioning, motor dysfunction, communication deficit. Time to postprogression deterioration was similar for MMSE, but for KPS it tended to be prolonged in the standard arm receiving crossover BEV/(IRI) (p = 0.09). CONCLUSION: Except for IRI-induced nausea/vomiting, first-line BEV/IRI therapy was not associated with any detrimental effects on QoL, performance status or cognition as compared to TMZ standard therapy. After progression, patients pretreated with TMZ in the standard arm had a prolonged stabilization of QoL in many dimensions presumably due to a high rate of crossover BEV therapy.

O10.04 * THE RANDOMIZED, MULTICENTER GLARIUS TRIAL INVESTIGATING BEVACIZUMAB/IRINOTECAN VS STANDARD TEMOZOLOMIDE IN NEWLY DIAGNOSED, MGMT-NON-METHYLATED GLIOBLASTOMA PATIENTS: FINAL SURVIVAL RESULTS AND QUALITY OF LIFE

BACKGROUND: There is a need for more effective therapies in newly diagnosed glioblastoma (GBM) patients with an MGMT-non-methylated tumor. The GLARIUS trial explored the efficacy of bevacizumab (BEV) + Irinotecan (IRI) as compared to standard TMZ in the first-line therapy of MGMT-non-methylated GBM. The primary endpoint progression-free survival after 6 months (PFS-6) has already been reported as being markedly increased in the BEV/IRI arm (Herrlinger et al., ASCO 2013, LBA 2000). The present report focuses on progression-free survival, overall survival (OS) and quality of life (QoL). METHODS: Patients (n = 170) with newly diagnosed, MGMT-non-methylated glioblastoma received local radiotherapy (RT, 30 x 2 Gy) and were randomized (2:1) for experimental therapy with BEV (10 mg/kg q2w) during RT followed by maintenance BEV (10 mg/kg q2w) + IRI (125 mg/m2 q2w) or standard therapy with daily TMZ (75 mg/m2) during RT followed by 6 courses of TMZ (150-200 mg/m2/day for 5 days q4w). For 5 prespecified dimensions of the EORTC-QLQ C30 and BN20 questionnaires (global health status, physical functioning, social functioning, motor dysfunction, communication deficit as prespecified domains), the time to deterioration by at least 10 points was analyzed using Kaplan-Meier statistics. RESULTS: With BEV/IRI, PFS was significantly prolonged from a median of 5.9 months (95%CI 2.7-6.2 months) to 9.7 months (95%CI 8.5-10.6 months, p < 0.0001; hazard ratio 0.57, 95%CI 0.41-0.79). At progression, the crossover rate was 60.4% (TMZ to BEV/(IRI) and 61.9% (BEV/IRI to TMZ). OS did not show any difference between the two arms: median OS was 16.6 months (95%CI 15.4-18.35 months) in the BEV/IRI arm and 17.3 months (95%CI 14.8-20.4 months). In all prespecified dimensions of QoL, the time to deterioration was not significantly different between the treatment arms. CONCLUSION: BEV/IRI therapy was superior to TMZ regarding PFS but OS was not prolonged. BEV/IRI therapy did not alter QoL as compared to TMZ therapy.

Survival and quality of life in the randomized, multicenter GLARIUS trial investigating bevacizumab/irinotecan versus standard temozolomide in newly diagnosed, MGMT-non-methylated glioblastoma patients.

2042^ Background: There is a need for more effective therapies in newly diagnosed glioblastoma (GBM) patients with an MGMT-non-methylated tumor. The GLARIUS trial explored the efficacy of bevacizum...

Update on neurooncology Annual meeting of the American Society of Clinical Oncology (ASCO) 2013

At this yearʼs American society of clinical oncology (ASCO) meeting (2013) a number of recently completed randomized Phase II and III trials regarding the treatment of high- and low-grade glioma were reported. The RTOG 0825 trial and the AVAglio trial, both double-blinded, placebo-controlled Phase III trials, addressed the benefits of bevacizumab in newly diagnosed glioblastoma (GBM) alongside to the standard of care (SOC). In the randomized Phase II GLARIUS trial, bevacizumab and irinotecan was compared to the SOC in GBM with a nonmethylated O6-Methylguanine-DNA Methyltransferase (MGMT) promoter. In the recurrent setting results from the Dutch BELOB randomized three arm phase II trial were presented: Bevacizumab alone vs. lomustine alone vs. the combination in recurrent GBM. The CENTRIC trial tested the integrin inhibitor cilengitide in newly diagnosed and MGMT promoter methylated GBM. Two trials on low-grade glioma (LGG) were presented: the single arm RTOG 0424 phase II trial for LGG with at least three risk factors and first results from the randomized phase III EORTC 22033-26033 trial, including LGG patients with one or more risk factors treated either with irradiation alone or temozolomide alone. Translational research results of these trials will be expected at a later point of time.

Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-nonmethylated glioblastoma patients: First results from the randomized multicenter GLARIUS trial.

LBA2000 Background: In patients with MGMT-nonmethylated glioblastoma (GBM), primary chemotherapy with temozolomide (TMZ) is at best moderately effective. There is an urgent need for more effective therapies in this large subgroup of GBM. Since results of phase II trials with the antiangiogenic agent bevacizumab (BEV) +/- irinotecan (IRI) are promising in recurrent GBM, the GLARIUS trial explored the efficacy of BEV/IRI as compared to standard TMZ in the first-line therapy of MGMT-non-methylated GBM. Methods: In the randomized, multicenter, open-label GLARIUS trial, adult patients with newly diagnosed, histologically confirmed and MGMT-non-methylated GBM received local radiotherapy (RT, 30 x 2 Gy) and were randomized (2:1) for experimental therapy with BEV (10 mg/kg q2w) during RT followed by maintenance BEV (10 mg/kg q2w) + IRI (125 mg/m² q2w (without enzyme-inducing antiepileptic drugs (EIAEDs)) or 340 mg/m² (with EIAEDs)) or standard therapy with daily TMZ (75 mg/m2) during RT followed by 6 courses of TMZ (150-200 mg/m2/day for 5 days q4w). The primary endpoint was progression-free survival rate after 6 months (PFS-6) as determined by central neuroradiological review. Results: The intent-to-treat population included 170 patients (67.1% male, median age 56 years (range 25-78 years), 48.8% complete resection rate, 78.8% of patients with KPS 90% or higher); 116 patients received BEV/IRI, 54 patients had TMZ. The frequencies of adverse events in both arms of the trial were within the expected range. The PFS-6 rate was significantly higher in the BEV/IRI arm (71.1%, 95% CI 58.1-80.8%) than in the TMZ arm (26.2%, 95% CI 13.1-41.4%, p&lt;0.0001 logrank test). Conclusions: The significant and clinically meaningful increase in the primary endpoint PFS-6 upon BEV/IRI chemotherapy suggests that BEV/IRI is superior to standard TMZ therapy in newly diagnosed MGMT-nonmethylated GBM patients. Clinical trial information: 2009-010390-21.

Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-non-methylated glioblastoma patients: First results from the randomized multicenter GLARIUS trial.

LBA2000 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.