National Horizon Scanning Centre. Bevacizumab (Avastin) for glioblastoma multiforme - relapsed. August 2008

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1 Bevacizumab (Avastin) for glioblastoma multiforme - relapsed August 2008 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 Research Programme is part of the National Institute for Health Research

2 Bevacizumab (Avastin) for glioblastoma multiforme - relapsed Target group Glioblastoma multiforme (GBM): relapsed first or second line; alone or in combination with irinotecan. Technology description Bevacizumab (Avastin) is a humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits VEGF-induced signalling and inhibits VEGF-driven angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Bevacizumab is administered as an intravenous infusion (IV) 10mg/kg every 2 weeks until disease progression with irinotecan 340mg/m 2 if enzyme inducing anti-epileptic drugs prescribed, or 125mg/m 2 if non-enzyme inducing anti-epileptic drugs are used. Bevacizumab is currently licensed for: Metastatic breast cancer: first line treatment in combination with paclitaxel. Metastatic carcinoma of colon and rectum: in combination with fluoropyrimidinebased chemotherapy. Non-small cell lung cancer (unresectable advanced, metastatic or recurrent other than predominantly squamous cell histology): first line treatment in addition to platinum-based therapy. Advanced and/or metastatic renal cell cancer: first line in combination with interferon alfa-2a. Innovation and/or advantages Bevacizumab may prolong disease-free progression and improve overall survival for people with relapsed GBM. Developer Roche Products Ltd. Availability, launch or marketing dates, and licensing plans: In phase III clinical trials. NHS or Government priority area: This topic is relevant to the NHS Cancer Plan (2000). Relevant guidance NICE terminated technology appraisal. Carmustine implants for the treatment of recurrent glioblastoma multiforme NICE technology appraisal. Carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma NICE technology appraisal. Temozolomide for the treatment of recurrent malignant glioma NICE Cancer service guidance. Improving outcomes for people with brain and other central nervous system tumours Clinical need and burden of disease Malignant glioma is the most common form of brain tumour, representing 50-60% of all primary brain tumours 3. There are three main types of glioma: astrocytoma, ependymoma and oligodendroglioma. Brain tumours are graded according to their likely rate of growth, 2

3 from grade I (slowest growing) to grade IV (fastest growing), with grades III and IV considered high-grade gliomas. Grade IV astrocytoma is also known as glioblastoma multiforme (GBM) 5. The annual incidence of malignant brain tumours in people aged 15 years and over, in England and Wales is 8.5 per 100,000 population (about 3,500 new cases each year). Approximately 1,860 new cases of malignant glioma are diagnosed each year in England and Wales. GBM accounts for approximately 40 45% of high grade gliomas 5, around 740 to 840 cases a year. A large proportion of these cases will go on to relapse after first and second line treatment a. Brain cancer is more common in males, with a male:female ratio of around 3:2 5. In 2005, 2,953 registered deaths from brain cancer were reported 6. The median survival of patients with GBM is 10 to 12 months from initial diagnosis 5. Existing comparators and treatments Surgical resection (rarely curative) Radiotherapy Chemotherapy e.g. temozolomide, camustine implants Efficacy and safety Conference abstracts have been identified in patients with GBM treated with bevacizumab in combination with etoposide 7, cetuximab 8, erlotinib 9 and temozolomide 10. Several studies are ongoing in patients with both grade III and IV disease. Trial code, name, phase BRAIN: Recurrent GBM; non-comparative; phase II 11. Recurrent malignant glioma; cohort; phase II 12. Sponsor Genentech Duke University; Genentech; NCI; NIH Status Published abstract. Published abstract. Location USA USA Design Randomised, single-arm. Non-randomised, cohort. Participants in trial n=167; recurrent GBM. Randomised to bevacizumab 10mg/m 2 every 2 weeks (BV); or BV 10mg/kg every 2 week and irinotecan (CPT) for 104 weeks or until progression. Follow-up 17 months. 32 months. Primary Progression free survival at 6 months PFS6; median OS. outcome (PFS6); objective response rate determined Secondary outcomes Key results by radiology (ORR). Safety; progression free survival; duration of response determined by radiology; overall survival (OS). PFS6: BV 35.1% (97.5% CI ) vs. BV+CPT 50.2% (CI ). ORR: BV 20% (CI ) vs. BV+CPT 32.9% (CI ). OS months: BV 9.7 months (CI ) vs. BV+CPT 8.9 months (CI ). n=68; recurrent malignant gliomas (35 with grade IV b and 33 with grade III tumours). 1 st cohort (n=32) 13 : BV (10mg/kg) every other week and CPT. 2 nd cohort (n=36) 13 : BV 15mg/kg on days 1 and 22 and CPT on days 1, 8, 22 and 29. Grade IV GBM: median PFS 23 weeks (95% CI 17-34) 13 and 2 year OS 15%. a Expert opinion. b Patient group relevant to briefing. 3

4 Adverse effects Grade 3 toxicities: BV 47.6%; BV+CPT 67.1%. Grade 5 adverse events: BV 2.4% vs. BV+CPT 1.3%. For all patients: one CNS haemorrhage after 10 treatment cycles. Eight patients taken off study due to thrombotic complications (2 deaths: one pulmonary embolism and one stroke). Trial code, Refractory GBM 14 Recurrent GBM 15 name, phase Sponsor Academic centre Academic centre Status Published abstract. Published abstract. Location Germany USA Design Non-randomised, non-controlled. Non-comparative, non-controlled trial Participants in trial n=44; progressive GBM resistant to temozolomide. BV (4mg/kg) and CPT 80mg/m 2 repeated every 2 weeks. n=22. Recurrent GBM. BV 5mg/kg and CPT 125mg/m 2 every 2 weeks. Follow-up Median follow-up seven months. Until disease progression or toxicity. Primary outcome Response evaluation criteria in solid tumours (RECIST). Median Length of Survival (LOS); Median time to progression (TTP). Secondary outcomes Key results Partial response (PR): 22 with median duration 3 months (2-8). Stabilised disease for at least 2 months: 15. Progressive disease (PD): 7. Adverse effects 1 death related to clostridium sepsis; 1 grade III leucopenia; 2 grade III thrombopenia; 1 grade III pneumonia; 2 intracerebral bleeds; 1 grade III fatigue. Median LOS: 4.6 months (range ) Median TTP: 3 months ( ). 2 grade III thrombocytopenia; 1 grade 3 neutropenia. Estimated cost and cost impact For an average person of 67.5kg, the cost per dose of bevacizumab 10mg/kg every 2 weeks is approximately 1,849 c. In addition, for patients given irinotecan, 125mg/m 2 to 340mg/m 2 (dependant on epileptic drug treatment), there would be additional costs of 313 to 780. For three months of treatment, the cost of bevacizumab would be 12,017 and for combination therapy between 14,052 and 17,087. Potential or intended impact speculative Patients Reduced morbidity Quicker, earlier or more accurate diagnosis or identification of disease Services Increased use: repeated IV infusions. Reduced mortality or increased survival Other: Service reorganisation required Improved quality of life for patients and/or carers None identified Staff or training required Decreased use Other: None identified c Costs from BNF 55. March 2008; assuming wastage. 4

5 Costs Increased unit cost compared to alternative New costs: additional to current options. Increased costs: more patients coming for treatment Savings: Increased costs: capital investment needed Other: References 1 National Institute for Health and Clinical Excellence. Carmustine implants for the treatment of recurrent glioblastoma multiforme. Terminated appraisal TA149. June National Institute for Health and Clinical Excellence. Carmustine implants and temozolomide for the treatment of newly diagnosed high grade glioma. Technology appraisal TA121. June National Institute for Health and Clinical Excellence. Temozolomide for the treatment of recurrent malignant glioma.technology appraisal TA23. April National Institute for Health and Clinical Excellence. Service guidance for improving outcomes for people with brain and other central nervous system tumours. Cancer service guidance. June National Institute for Health and Clinical Excellence. Final scope: Carmustine implants for the treatment of recurrent glioblastoma multiforme. Technology appraisal TA149. May Cancer Research UK. Cancer stats mortality UK Rich JN, Desjardins A, Sathornsumette S et al. Phase II study of bevacizumab and etoposide in patients with recurrent malignant glioma. American Society of Clinical Oncology Abstract number: Lassen U, Hasselbalch B, Sørensen M et al. A phase II trial with cetuximab, bevacizumab and irinotecan for patients with primary glioblastomas and progression after radiation therapy and temozolomide. American Society of Clinical Oncology Abstract number: Sathornsumetee S. Vredenburgh JJ, Rich JN et al. Phase II study of bevacizumab and erlonitinib in patients with recurrent glioblastoma multiforme. American Society of Clinical Oncology Abstract number: Maron R, Vredenburgh JJ, Desjardins A et al. Bevacizumab and daily temozolomide for recurrent glioblastoma multiforme (GBM). American Society of Clinical Oncology Abstract number: Cloughesy TF, Prados MD, We PY et al. A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). American Society of Clinical Oncology Abstract number: 2010b 12 Wagner SA, Desjardins A, Reardon DA et al. Update on survival from the original phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. American Society of Clinical Oncology Abstract number: Goli KJ, Desjardins A, Herndon JE et al. Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomas. American Society of Clinical Oncology Abstract number: Dresemann A, Hobbold A, Dresemann. Bevacizumab (B) plus irinotecan (I) in progressive multiple pretreated and temozolomide (T) refractory glioblastoma multiforme (GBM): a single center experience using a low dose regime. American Society of Clinical Oncology Abstract number: Raval S, Hwang S, Dorsett L. Bevacizumab and irinotecan in patients (pts) with recurrent glioblastoma multiforme (GBM). American Society of Clinical Oncology Abstract number: The National Institute for Health Research Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0)