Elsevier

The Lancet Oncology

Volume 15, Issue 10, September 2014, Pages 1100-1108
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(14)70379-1Get rights and content

Summary

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.

Introduction

Glioblastoma is the most common histological subtype of primary malignant brain tumour, with an annual incidence of about three per 100 000.1 Glioblastomas are also the most aggressive form of primary brain tumour, with a dismal median survival of less than 12 months in population-based studies, and median survival of 15–17 months in clinical trials.2, 3, 4 The standard treatment for patients with newly diagnosed glioblastoma consists of surgery followed by temozolomide chemoradiotherapy (radiotherapy with concomitant and adjuvant temozolomide).2, 5 Other chemotherapeutics have little activity because of inherent resistance of glioblastoma cells against most cytotoxic drugs, or the inability of the drugs to cross an intact blood–brain barrier and reach their target.6, 7

The DNA repair protein MGMT is an important prognostic factor in glioblastoma; its presence has been associated with decreased survival and resistance to alkylating chemotherapy.8 Epigenetic silencing of the MGMT gene by promoter methylation can lead to it subsequently being unable to protect tumours from cytotoxic damage induced by temozolomide, and thus predicts benefit from temozolomide chemotherapy.9 In a pivotal randomised trial10 investigating the value of temozolomide added to radiotherapy in patients with glioblastoma, median survival in patients with methylated MGMT promoter increased from 15·3 months (95% CI 13·0–20·9) with radiotherapy alone to 21·7 months (17·4–30·4) with radiotherapy and temozolomide (hazard ratio [HR] 0·51, 95% CI 0·31–0·84). However, patients with unmethylated MGMT promoter in the tumour showed only a marginal benefit from addition of temozolomide, with a median survival of 12·7 months (95% CI 11·6–14·4) compared with 11·8 months (9·7–14·1) for patients treated with radiotherapy alone (HR 0·69, 95% CI 0·47–1·02).

Although glioblastomas very rarely metastasise, they frequently have local recurrence not only at the edge of resection but also at distant locations within the brain. Glioblastoma cells are characterised by high motility and invasiveness, requiring complex cell–matrix interactions.11 Integrins are a family of cell–cell and cell–extracellular matrix adhesion molecules, implicated in various cellular processes (eg, cell survival, proliferation, migration, invasion, and angiogenesis), and thus can support tumour development.12 In particular, αvβ3 and αvβ5 integrins are thought to be key mediators of crosstalk between tumour cells and the brain microenvironment in glioblastoma, and are overexpressed on tumour cells and vasculature.13, 14, 15 Therefore, targeting of integrins and the tumour microenvironment is considered a promising therapeutic strategy in glioblastoma.15, 16

Cilengitide is a selective inhibitor of αvβ3 and αvβ5 integrins.17 In phase 1/2 studies in patients with recurrent or newly diagnosed glioblastoma, cilengitide alone or in combination with temozolomide chemoradiotherapy was well tolerated and showed potential antitumour activity.18, 19, 20, 21, 22 In a multicentre phase 1/2 study20 of cilengitide added to standard temozolomide chemoradiotherapy in 52 patients with newly diagnosed glioblastoma, survival analyses suggested improved outcome compared with historical controls in patients with methylated MGMT gene promoter in the tumour, suggestive of synergy between cilengitide and temozolomide chemotherapy in chemosensitive tumours. Patients with and without MGMT promoter methylation had median progression-free survival of 13·4 and 3·4 months (HR 0·26, 95% CI 0·13–0·51, p<0·001), and a median overall survival of 23·2 and 13·1 months (HR 0·44, 95% CI 0·21–0·91, p=0·022), respectively.20 Furthermore, findings from two randomised phase 2 studies showed improved survival for patients with glioblastoma treated with higher dose cilengitide (2000 mg) than for those given a lower dose (500 mg), in both the newly diagnosed and recurrent setting.19, 21 Preclinical models have also shown synergistic activity of cilengitide and irradiation.23 In a randomised phase 3 trial, we aimed to assess cilengitide combined with standard treatment in a subgroup of patients with glioblastoma with methylated MGMT promoter. The investigation of patients with an unmethylated MGMT promoter in the tumour was subject of an exploratory phase 2 study (CORE) initiated shortly after our study began.24

Section snippets

Study design and participants

The CENTRIC trial was a global, multicentre, randomised, open-label, phase 3 trial. Eligible patients were aged 18 years or older with newly diagnosed, histologically confirmed supratentorial glioblastoma (WHO grade IV), methylated MGMT promoter as determined by a central laboratory, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Additional inclusion criteria were written informed consent; available tumour tissue from surgery or open biopsy (stereotactic

Results

3471 patients were registered and screened for eligibility; of these patients, 3060 were assessed for MGMT methylation status. Patients were recruited at 146 study sites in 25 countries worldwide. 926 patients had glioblastoma with MGMT gene promoter methylation, including 382 patients who did not to continue to randomisation (figure 2). 545 patients were randomly assigned to a treatment group between Oct 31, 2008, and May 12, 2011, and constituted the intention-to-treat population. Patient

Discussion

Findings from this large, prospective, phase 3 trial investigating the first-in-class integrin inhibitor cilengitide as antitumour therapy in combination with standard chemoradiotherapy did not show improved outcomes. Neither progression-free survival nor overall survival were significantly prolonged, and an HR of 1·02 for overall survival suggests absence of any activity. The median overall survival of 26·3 months that we noted in both treatment groups is consistent with previous reports and

References (33)

  • KA Jaeckle et al.

    Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study

    J Clin Oncol

    (1998)
  • ME Hegi et al.

    Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide

    Clin Cancer Res

    (2004)
  • ME Hegi et al.

    MGMT gene silencing and benefit from temozolomide in glioblastoma

    N Engl J Med

    (2005)
  • DB Hoelzinger et al.

    Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment

    J Natl Cancer Inst

    (2007)
  • DG Stupack

    The biology of integrins

    Oncology (Williston Park)

    (2007)
  • L Bello et al.

    α(v)β3 and α(v)β5 integrin expression in glioma periphery

    Neurosurgery

    (2001)
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