This trial has shown the feasibility of upfront central histological review and molecular testing with no substantial delay in an international multicentre trial setting, which is a prerequisite for further drug development towards personalised medicine.
—Roger Stupp, MD, and colleagues
In the phase III CENTRIC/European Organisation for Research and Treatment of Cancer (EORTC) 26071-22072 trial reported in The Lancet Oncology, Roger Stupp, MD, of University Hospital Zurich, and colleagues found that adding the selective αvβ3 and αvβ5 integrin inhibitor cilengitide to standard temozolomide chemoradiotherapy produced no survival benefit in patients with newly diagnosed glioblastoma and methylated MGMT promoter.1 The authors stated that development of cilengitide as an anticancer agent has been halted.
Cilengitide is a selective inhibitor of αvβ3 and αvβ5 integrins, which appear to mediate communication between glioblastoma cells and the brain microenvironment and are overexpressed on tumor cells and vasculature. These cell-cell and cell-matrix adhesion molecules are involved in angiogenesis, as well as in cellular survival, proliferation, migration, and invasion. Since glioblastoma cells exhibit high motility and invasiveness mediated by cell-matrix interactions, integrins are a target in drug development.
Methylation of the promoter for MGMT, which encodes the DNA repair protein MGMT, preserves sensitivity of glioblastoma to the cytotoxic effects of temozolomide. Phase I/II data suggested a potential synergistic effect of cilengitide and temozolomide in glioblastoma with MGMT promoter methylation. Previous randomized trials assessing the addition of the antiangiogenic agent bevacizumab (Avastin) to standard temozolomide and radiotherapy in newly diagnosed glioblastoma have shown improved progression-free survival but not overall survival.
CENTRIC Trial Details
The CENTRIC trial was an international endeavor including investigators from the EORTC and the Canadian Brain Tumor Consortium, as well as researchers from South Korea, India, and the United States, among others.
For patients with newly diagnosed glioblastoma, standard treatment includes surgery followed by temozolomide chemoradiotherapy (radiotherapy with concomitant and adjuvant temozolomide). In this open-label trial, 545 adult patients (from 3,471 screened) from 25 countries were treated with surgery and were randomly assigned between October 2008 and May 2011 to receive temozolomide chemoradiotherapy with intravenous cilengitide at 2,000 mg twice weekly (n = 272) or temozolomide chemoradiotherapy alone (n = 273). Prior to randomization, an independent pathology review was performed and MGMT promoter methylation status was centrally determined.
Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxicity. Randomization was stratified for prognostic Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis class and geographic region. The primary endpoint was overall survival analyzed in the intention-to-treat population.
The cilengitide and control groups were generally balanced for age (median, 58 years in both), sex (54% and 52% male), region (North America for 12% in both, Europe for 68% and 67%), Eastern Cooperative Oncology Group performance status (0 in 57% and 55%, ≥ 1 in 43% and 44%), RTOG recursive partitioning analysis class (III in 16% and 15%, IV in 68% and 63%, V in 16% and 20%), Mini-Mental State Examination score (≥ 27 in 83% and 76%), extent of resection (gross total in 49% and 50%, partial in 48% and 47%, biopsy in 3% in both), antiepileptic use (enzyme-inducing antiepileptic drug [EIAED] in 20% and 21%, non-EIAED only in 36% and 44%, none in 44% and 34%), steroid use (38% and 41%), and weeks from diagnosis to radiotherapy (median, 6.2 and 5.4).
No Survival Differences
Median overall survival was 26.3 months (95% confidence interval [CI] = 23.8–28.8 months) in the cilengitide group vs 26.3 months (95% CI = 23.9–34.7 months) in the control group (hazard ratio [HR] = 1.02, P = .86) and was similar in the two groups irrespective of stratification factors. Two-year overall survival was 56% in both groups.
Median progression-free survival was 13.5 vs 10.7 months (HR = 0.93, P = .46) on investigator assessment and 10.6 vs 7.9 months (HR = 0.92, P = .41) on independent radiologic review committee assessment at an average of one assessment time point earlier in each group. No benefit of cilengitide for overall or progression-free survival was observed in any predefined patient subgroups.
The most common adverse events of any grade in the cilengitide group were nausea (49% vs 49% in control group), headache (45% vs 34%), fatigue (39% vs 33%), and constipation (39% vs 30%). The most common adverse events of grade ≥ 3 were lymphopenia (12% vs 10%), thrombocytopenia (11% vs 18%), neutropenia (7% vs 9%), leukopenia (7% vs 8%), and convulsion (5% vs 6%). Grade 3/4 hemorrhage occurred in 2% of both groups.
Serious adverse events occurred in 52% vs 45%, and adverse events leading to death occurred in 4% vs 3%. Three deaths in each group (1%) were considered treatment-related, consisting of two deaths due to pulmonary embolism and one due to aspiration pneumonia in the cilengitide group, and deaths due to pancytopenia/pneumonia, pneumonia, and septic shock in the control group.
The investigators concluded: “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.”
The authors noted that the CENTRIC trial involved screening and molecular assessment of nearly 3,500 patients with a relatively rare disease over the course of 2 years and that, despite the time required for molecular assessment, the median time to treatment was only 5 to 6 weeks. In this regard, they stated: “This trial has shown the feasibility of upfront central histological review and molecular testing with no substantial delay in an international multicentre trial setting, which is a prerequisite for further drug development towards personalised medicine.” ■
Disclosure: The study was funded by Merck KGaA. For full disclosures of the study authors visit www.thelancet.com/oncology.
1. Stupp R, Hegi ME, Gorlia T, et al: 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. Lancet Oncol 15:1100-1108, 2014.
Temozolomide in combination with radiation for newly diagnosed glioblastoma was approved by the U.S. Food and Drug Administration in 2005—almost 10 years ago—but we have unfortunately made little progress in improving survival for this incurable brain tumor. Despite recent completion of three...