No Benefit of Adding Cilengitide in Glioblastoma With Methylated MGMT Promoter
In the phase III CENTRIC EORTC 26071-22072 trial reported in The Lancet Oncology, Stupp et al found that adding the selective αvβ3 and αvβ5 integrin inhibitor cilengitide to standard temozolomide chemoradiotherapy produced no survival benefit in newly diagnosed glioblastoma with methylated MGMT promoter. The authors stated that development of cilengitide as an anticancer agent has been halted.
Inhibition of the αvβ3 and αvβ5 integrins, which are thought to mediate communication between tumor cells and the brain microenvironment in glioblastoma and are overexpressed on tumor cells and vasculature, is intended to inhibit angiogenesis and such other cellular processes as survival, proliferation, migration, and invasion. Phase II data had shown activity of single-agent cilengitide in recurrent glioblastoma and particular activity in combination with standard therapy in newly diagnosed disease with methylated MGMT promoter.
Study Details
In this open-label trial, 545 adult patients (from 3,471 screened) from 25 countries were randomly assigned between October 2008 and May 2011 to receive temozolomide chemoradiotherapy with cilengitide at 2,000 mg intravenously twice weekly (n = 272) or temozolomide chemoradiotherapy alone (n = 273). 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 in 20% and 21%, non–enzyme-inducing antiepileptic drug 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. 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 survival or progression-free survival was observed in any predefined patient subgroups.
Toxicity
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 or 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 to aspiration pneumonia in the cilengitide group and deaths due to pancytopenia and 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.”
Roger Stupp, MD, of University Hospital Zurich, is the corresponding author for The Lancet Oncology article.
The study was funded by Merck KGaA. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
