ArticlesCilengitide 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
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)
- et al.
EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma
Lancet Oncol
(2014) - et al.
Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma
J Mol Diagn
(2008) - et al.
Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial
Lancet Oncol
(2012) - et al.
Assessment of the biological and pharmacological effects of the α ν β3 and α ν β5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors
Ann Oncol
(2007) - et al.
CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009
Neuro-Oncol
(2012) - et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
N Engl J Med
(2005) - et al.
Glioblastoma survival in the United States before and during the temozolomide era
J Neuro Oncol
(2012) - et al.
Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial
J Clin Oncol
(2013) - et al.
Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain
Expert Rev Mol Med
(2011) - et al.
Drug resistance in glioblastoma: a mini review
Neurochem Res
(2012)