The results of this analysis do not justify the use of VPA or LEV for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.

No abstract

PURPOSE: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methlyguanine-DNA-methlytransferase (MGMT) promoter. PATIENTS AND METHODS: Patients (n=257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n=111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A non-comparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Pre-specified post hoc analyses of markers reflecting target activation were performed. RESULTS: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% 2)] in the temozolomide arm and 69.6% ] in the temsirolimus arm [HR=1.16, p=0.47]. In multivariable prognostic analyses of clinical and molecular factors phosphorylation of mTORSer2448 in tumor tissue (HR=0.13, 95% CI (0.04-0.47), p=0.002), detected in 37.6%, was associated with benefit from temsirolimus. CON-CLUSIONS: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on May 3, 2016; DOI: 10.1158/1078-0432.CCR-15-3153 EORTC 26082 Wick et al. Page 2 2/26/

2006 Background: Radiotherapy with concomitant and adjuvant TMZ (TMZ/RT TMZ) is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. Compared with the standard adjuvant TMZ, dd TMZ results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial determined if intensified TMZ improves survival (OS) or progression free survival (PFS). Methods: This phase III trial was conducted by the RTOG, EORTC and NCCTG. Neurologically stable patients with adequate tissue for prospective MGMT analysis were randomized to Arm 1: standard TMZ (150-200 mg/m 2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m 2 x 21 d) q 4 wks for 6-12 cycles. Symptom, QOL and neurocognitive testing was performed in a subset of patients. The primary endpoint was OS. Secondary analyses evaluated impact of MGMT status. Eligibility criteria included age > 18 yrs, KPS 60, and tissue block with > 1cm 2 tumor. Results: A total of 833 patients were randomized from a total of 1173 registered. Inadequate tissue (n=144) and early disease progression (n =56) were the most frequent reasons for non-randomization. No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p = 0.63), or median PFS (5.5, 6.7 mo, p = 0.06), or by 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 response (p = 0.012). Cox modeling showed that MGMT status and RPA class were significant predictors of OS while the treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade 3 toxicity in Arm 2 (19%, 27%, p = 0.008); mostly lymphopenia and fatigue. Conclusions: 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. Additionally, it demonstrated the feasibility of tumor tissue collection, molecular stratification and collection of patient outcomes in a large transatlantic intergroup trial and established this as a viable clinical trial paradigm.

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LBA2009 Background: Cilengitide (CIL) is a selective αvβ3 and αvβ5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8). Methods: This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients (≥ 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determined MGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RT→TMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RT→TMZ alone. CIL was to be administered for ≥ 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety. Results: 272 patients received CIL plus TMZ/RT→TMZ, and 273 were treated with TMZ/RT→TMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS ≥ 1, respectively. 75% of patients of both arms were ≥ 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed. Conclusions: CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed. Clinical trial information: NCT00689221.

The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy and chemotherapy. For many systemic cancers, targeted treatments are a part of standard of care, however the predictive significance of most of these targets in CNS tumors remains less well studied. Despite that, there is an increasing use of advanced molecular diagnostics that identify potential targets, and tumor agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, FGFR, NTRK, PDGFRA, ROS1), in cell cycle signaling (CDK4/6, MDM2/4, TSC1/2) and altered genomic stability (mismatch repair, POLE, high TMB, HRD) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials.

Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens