Comment 1044 www.thelancet.com/oncology Vol 15 September 2014 to fully resolve these issues. Previous research has shown that combination treatment might be the most successful means to eradicate several blood cancers: CLL is seemingly no exception. Paolo Ghia Division of Molecular Oncology and Department of Onco-Hematology, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan 20132, Italy ghia.paolo@hsr.it I have received personal fees from Pharmacyclics, Gilead, Merck, Boehringer Ingelheim, and AbbVie, and grants from Roche Italy and GSK. 1 Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42. 2 Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood 2014; 123: 3390–97. 3 Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371: 213–23. 4 Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370: 997–1007. Cilengitide in glioblastoma: when did it fail? Angiogenesis and invasion are both crucial for tumour growth, although more anti-angiogenic drugs have been developed than have drugs with mainly anti- invasive properties. Integrins are a large family of molecules involved in signalling between cells and stromal components, implicated in various processes including tumour angiogenesis and invasion. Many of their receptors are active in both normal and cancerous cells; these molecules are therefore challenging to target. The integrin αvβ3, involved in angiogenesis in addition to cell migration and proliferation, is expressed at low levels in normal cells and overexpressed in glioblastoma, melanoma, breast, prostate, and pancreatic cancer cells. Cilengitide, one of the few anti-integrin drugs developed to date, selectively inhibits αvβ3 and αvβ5. In The Lancet Oncology, Roger Stupp and colleagues 1 report the negative results of the CENTRIC phase 3 trial, which assessed the benefit of cilengitide addition to standard care (radiotherapy with concomitant and adjuvant temozolomide chemotherapy) in patients with newly diagnosed glioblastoma. This trial was restricted to patients whose tumour had methylated MGMT promoter, an important favourable prognostic factor. Overall survival was similar in both groups (26·3 months [95% CI 23·8–28·8] in the cilengitide group vs 26·3 months [23·9–34·7] in the control group; hazard ratio 1·02, 95% CI 0·81–1·29, p=0·86). Additionally, progression-free survival analysis did not detect any activity that could have been diluted in the survival analysis. Although disappointing at this stage of development, these results are in line with the lack of activity of the drug as reported in randomised phase 2 trials in other cancers, leading the drug manufacturer to halt further development of the compound as a cancer treatment. After such a large effort from all parties, including patients, on a study that benefited from collaboration between industry and academia, how can we interpret these results? First, although the αvβ3 integrin is present and overexpressed in glioblastoma, targeting of this molecule is complex because of the dose- dependent opposing effects of cilengitide: low doses have been reported to stimulate blood vessel growth and tumour angiogenesis, by contrast with inhibition at higher doses. 2 The two dosing schedules of 500 mg and 2000 mg that have been used in trials of cilengitide in various cancers might not fully reflect the complexity of this dual effect. Second, metabolic imaging and tissue analysis support the suggestion that cilengitide reaches its target; however, little is known about the biological effect of the drug on tumour vasculature or invasiveness in patients. The effects on tumour cell apoptosis and Published Online August 20, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70403-6 See Articles page 1100 Zephyr/Science Photo Library 5 Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol 2014; published online Aug 19. http://dx.doi.org/10.1016/S1470-2045(14)70335-3. 6 Woyach JA, Smucker K, Smith LL, et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014; 123: 1810–17. 7 Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood 2012; 119: 1182–89. 8 O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2014; 15: 48–58. 9 Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab- dependent NK cell-mediated cytotoxicity. Blood 2014; 123: 1957–60. 10 Da Roit, Engelberts PJ, Taylor RP, et al. Ibrutinib interferes with the cell- mediated anti-tumour activities of therapeutic CD20 antibodies: implications for combination therapy. 19th Congress of the European Hematology Association; Milan, Italy; June 12–15, 2014. Abstract 1342. 11 Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013; 122: 2539–49. 12 Bologna L, Gotti E, Manganini M, et al. Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab. J Immunol 2011; 186: 3762–69.