Cilengitide (Impetreve) for glioblastoma multiforme February 2012 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research
Cilengitide (Impetreve) for glioblastoma multiforme Target group Glioblastoma multiforme (GBM): newly diagnosed in combination with standard therapy. Technology description Cilengitide (Impetreve; EMD-121977) is an inhibitor of integrins α v β 3 and α v β, which play a key role in cellular attachment to the extracellular matrix (ECM). The association between tumour-related blood vessels and the ECM is dependent on the ability of proliferating endothelial cells to interact with ECM glycoproteins, an interaction mediated by integrins α v β 3 and α v β 1. Inhibition of these endothelial transmembrane receptors acts directly on tumour cells leading to disassembly of the cytoskeleton, cellular detachment and induction of apoptosis 2. Proliferating endothelial cells express increased levels of α v β 3 in comparison with quiescent cells 1. In the phase III trial cilengitide was administered by intravenous (IV) infusion at 2,000mg twice weekly 3. Cilengitide is also in phase III trials for recurrent glioblastoma and in phase II trials for non-small cell lung cancer and squamous cell carcinoma of the head and neck. Innovation and/or advantages If licensed, cilengitide would represent the first in a new class of treatments for this patient group. Developer Merck Serono. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government priority area This topic is relevant to Improving Outcomes: A Strategy for Cancer (2011). Relevant guidance NICE technology appraisal. Carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma. 2007 4. NICE technology appraisal. Temozolomide for the treatment of recurrent malignant glioma (brain cancer). 2001. NICE cancer service guidance. Improving outcomes for people with brain and other 6 CNS tumours. 2006. NICE interventional procedure guidance. Photodynamic therapy for brain tumours. 2009 7. Clinical need and burden of disease Brain tumours are relatively rare, accounting for approximately 1.% of all malignant neoplasms in adults in England and Wales 8. Malignant gliomas represent 0-60% of all primary brain tumours, occurring at an approximate incidence rate of 3-4 per 100,000 population per year in England and Wales and leading to around 3,00 new cases per year in the UK. Anaplastic astrocytomas (30-3%) and GBM (40-4%) account for the majority of malignant gliomas, with anaplastic oligodendrogliomas (-1%) comprising the remaining cases. 2
In 2010-2011, there were 16,482 admissions for primary brain tumours in England, resulting in 107,9 bed days and 20,323 finished consultant episodes 9. In 2010, there were 3,38 registered deaths due to primary brain tumours in England and Wales (ICD C71) 10. Patients with malignant glioma suffer a range of symptoms which can have a severe detrimental impact on quality of life. General symptoms include raised intracranial pressure with headache, nausea and vomiting, seizures, and focal neurological deficits occasionally accompanied by more global changes such as drowsiness, changes in personality and cognition,a. Other specific focal deficit symptoms related to the location of the tumour can include difficulties with, speech, vision, ambulation, dexterity and mood disturbances,b. Following initial treatment for GBM, most patients will experience tumour recurrence with limited efficacy of available treatments; management is largely palliative 8,b. Median survival time from initial diagnosis is 11-12 months for GBM 8 and is principally related to age and performance status. Median survival of patients with good performance status treated with radical intent is in the region of 14 months, whilst the median survival in older patients is approximately 4-6 months b. Existing comparators and treatments Standard treatment consists of surgical resection, radiotherapy and adjunctive chemotherapy 8. Concomitant and adjuvant temozolomide is recommended by NICE as a treatment option for newly diagnosed GBM. Carmustine impregnated wafers are occasionally inserted into the resection cavity for patients in whom 90% or more of the tumour has been resected 4,b. Other chemotherapy regimens include oral procarbazine in combination with lomustine and vincristine (PVC) as well as single-agent lomustine 4,. Efficacy and safety Trial CENTRIC, NCT00689221, EMD 121974-011, EORTC 26071-22072; cilengitide in combination with temozolomide and radiation therapy vs temozolomide and radiation therapy CORE, NCT00813943, EMD 121974-012; cilengitide in combination with temozolomide and radiation therapy vs temozolomide and radiation therapy alone; phase II. alone; phase III. Sponsor EMD Serono. EMD Serono. Status Ongoing. Ongoing. Source of Trial registry 3. Trial registry 11. information Location EU and USA. USA. Design Open label, active-controlled. Open label, active-controlled. Participants and schedule n=04 (planned); adults; histologically confirmed GBM; methylated methylguanine-dna methyltransferase (MGMT) gene promoter status b. Randomised to IV cilengitide 2,000mg twice weekly in combination with temozolomide and radiotherapy or n=264 (planned); adults; histologically confirmed GBM; unmethylated MGMT gene promoter status. Arm 1 IV cilengitide 2,000mg twice weekly in combination with temozolomide and radiotherapy. a Expert personal communication b Methylguanine-DNA methyltransferase (MGMT) gene promoter status - MGMT is an enzyme that repairs DNA damage at a site commonly targeted by cytotoxic drugs, thereby inhibiting the effect of chemotherapy on tumours. MGMT promoter methylation has been associated with extended overall survival and progressionfree survival 4. 3
Follow-up Primary outcome Secondary outcome Expected reporting date temozolomide and radiotherapy alone. Temozolomide administered at 7mg/m 2 for 6 weeks (during radiation therapy) followed by a maintenance dose of 10-200mg/m 2 on days 1- of a 28 day cycle for a total of 6 cycles. Focal radiation therapy was administered times per week at 30x2.0Gy; total dose 60Gy. Continuous treatment until disease progression. Overall survival (OS) is monitored for a minimum of 3 years from randomisation. OS. Safety and tolerability, progression-free survival, quality of life, pharmacokinetics. Estimated primary completion date Sept 2012. Arm 2 IV cilengitide 2,000mg twice weekly, increased to 2,000mg five times per week during period of combined temozolomide and radiotherapy treatment. Arm 3 Temozolomide and radiotherapy alone. Temozolomide administered at 7mg/m 2 for 6 weeks (during radiation therapy) followed by a maintenance dose of 10-200mg/m 2 on days 1- of a 28 day cycle for a total of 6 cycles. Focal radiation therapy was administered times per week at 30x2.0Gy; total dose 60Gy. Continuous treatment until disease progression. OS is monitored for a minimum of 3 years from randomisation. OS. Safety and tolerability, progression-free survival, quality of life, pharmacokinetics. Estimated primary completion date March 2013. Estimated cost and cost impact The cost of cilengitide is not yet known. The cost of one carmustine implant is 8.34 12. Up to eight implants may be used simultaneously depending on the size and shape of the resection cavity following surgery. The cost of temozolomide administered at 7mg/m 2 daily for 42 days is 3,66.2 c, and then as monotherapy at 10mg/m 2 daily for days is 830.79 12. Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Services Increased use: twice weekly IV dosing schedule. Reduction in associated morbidity or improved quality of life for patients and/or carers Service organisation Quicker, earlier or more accurate diagnosis or identification of disease None identified Staff requirements Decreased use Other: None identified Costs Increased unit cost compared to alternative New costs: new additional treatment option. Increased costs: more patients coming for treatment Savings: Increased costs: capital investment needed Other: c Based on average surface area 1.7m 2 4
Other issues Clinical uncertainty or other research question identified None identified References 1 Eskens FA, Dumez H, Hoekstra R et al. Phase I and pharmacokinetic study of continuous twice weekly intravenous administration of cilengitide (EMD 121974), a novel inhibitor of the integrins α v β 3 and α v β in patients with advanced solid tumours. European Journal of Cancer 2003;39(7):917-926. 2 Oliveira-Ferrer L, Hauschild J, Fiedler W et al. Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway. Journal of Experimental and Clinical Cancer Research 2008;27(1):86. 3 ClinicalTrials.gov. Cilengitide, temozolomide, and radiation therapy in treating patients with newly diagnosed glioblastoma and methylated gene promoter status (CENTRIC). http://clinicaltrials.gov/ct2/show/nct00689221?term=nct00689221&rank=1 Accessed 11 January 2012. 4 National Institute for Health and Clinical Excellence. Carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma. Technology appraisal TA121. London: NICE; June 2007. National Institute for Health and Clinical Excellence. Temozolomide for the treatment of recurrent malignant glioma (brain cancer). Technology appraisal TA23. London: NICE; April 2001. 6 National Institute for Health and Clinical Excellence. Improving outcomes for people with brain and other CNS tumours. Cancer service guidance CSGBraincns. London: NICE; June 2006. 7 National Institute for Health and Clinical Excellence. Photodynamic therapy for brain tumours. Interventional procedure guidance IPG290. London: NICE; March 2009. 8 Dinnes J, Cave C, Huang S et al. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review. Health Technology Assessment 2001; Vol.:No.13. 9 NHS Hospital episode statistics. NHS England 2010-2011 HES data. 2011. www.hesonline.nhs.uk 10 Office for National Statistics. Mortality statistics deaths registered in 2010, series DR 2010 www.statistics.gov.uk 11 ClinicalTrials.gov. Cilengitide, temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma and unmethylated gene promoter status (CORE) http://clinicaltrials.gov/ct2/show/nct00813943 Accessed 13 January 2012. 12 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 62. London: BMJ Group and RPS Publishing, September 2011. The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B1 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon