The European Committee for Medicinal Products for Human Use (CHMP), which is responsible for conducting the initial assessment of medicinal products that have been filed for marketing authorization in Europe, has issued a negative opinion relating to the approval of bevacizumab (Avastin?, Roche, Basel, Switzerland), an antibody that specifically binds and blocks the biological effects of VEGF (vascular endothelial growth factor) a key driver tumor angiogenesis which is an essential process required for a cancer to metastasize, alone or in combination with irinotecan (Camptosar?, Pfizer, New York, USA) chemotherapy for the treatment of relapsed or progressive glioblastoma (GBM).Glioma is the most aggressive type of primary malignant brain cancer tumor, accounting for approximately one third of all cases diagnosed?. Glioma also represents around 80% of all primary malignant brain tumor cases?. Glioblastoma (or glioblastoma multiforme; GBM) is the most common and the most aggressive type of glioma?. The prognosis for patients with GBM is poor. The treatment options for GBM depend on many factors including the location and size of the tumour, and the overall health and age of the patient?Glioblastoma affects approximately 17,000 people per year in the EU?. Following initial treatment, glioblastoma tumours nearly always return and currently, there are limited treatment options for patients when these relapses occur and their prognosis is particularly poor?. According to historical estimates, less than 10% of patients with recurrent GBM respond to treatment and approximately 15% will live six months without their disease getting worse??GBM is a compelling therapeutic target for bevacizumab as these tumors have very high levels of vascular endothelial growth factor (VEGF)??.FilingThe drug filing by Roche, the manufacturer of the drug, was based on results from the phase II BRAIN study (AVF3708g)?, a US based open-label, multicentre, non-comparative phase II study including 167 patients with histologically confirmed GBM that had progressed following initial treatment with temozolomide and radiation.The primary endpoints of the BRAIN trial were progression free survival-6 (PFS-6), (defined as the percentage of patients who remained alive and progression free at 24 weeks) and objective response rate (ORR), (defined as a complete or partial response on two consecutive MRIs obtained 4 weeks apart). Secondary endpoints explored included OS, PFS, duration of response to treatment and safety. The BRAIN study evaluated bevacizumab at a dose of 10mg/kg every two weeks, as a single agent (BEV), or in combination with irinotecan chemotherapy (BEV-IRI).The study showed that when bevacizumab was evaluated as a single agent, the study showed that at six months over 40% (42.6%) of the patients were alive without their disease getting worse, as defined by PFS-6. When bevacizumab was combined with irinotecan, this figure increased to 50.3% ?.The study further showed that over a quarter (28%) of patients responded to bevacizumab as a single agent, meaning tumours decreased in size by at least 50%. When bevacizumab was combined with irinotecan, 38% of patients responded to bevacizumab?. Other results included:- Patients receiving bevacizumab alone had a median overall survival of 9.2 months; this was 8.7 months for those receiving bevacizumab in combination with irinotecan, which was a secondary endpoint in the study?.- Adverse events in the BRAIN study were consistent with those previously seen with bevacizumab and no new safety signals were reported?.- Recent results showed the potential for additional positive impact on patients? daily lives. Of those patients who responded to bevacizumab-based therapy, a majority had a stabilization or improvement in neurocognitive function at the time of the response and a reduction in their dose of steroids from baseline?.CHMP?s ObjectionThe CHMP was concerned that the company had not provided sufficient scientific evidence of the medicine?s benefits, because the number of patients who responded to treatment was not dramatic and because response rates may not be a suitable measure of the medicine?s effectiveness. In addition, the CHMP could not interpret the findings on survival because the BRAIN study, an investigational phase II trial, did not compare bevacizumab directly with any other treatments.Therefore, at that point in time, the CHMP was of the opinion that the balance of benefits and risks of bevacizumab in the treatment of glioblastoma after relapse could not be established. Hence, the CHMP recommended that the change to the marketing authorization be refused.Generally, the CHMP tends to base its approval decisions on Phase III studies only. Therefore, Roche, decided to submit this data set to regulatory authorities globally based on bevacizumab?s remarkable clinical activity seen in BRAIN.While the CHMP offered a negative advice, the company remains convinced that the results of the BRAIN study, which were published in the Journal of Clinical Oncology in October 20091 are robust and remain valid. Adverse events in the BRAIN study were consistent with those previously seen with bevacizumab and no new safety signals were reported.??We are very disappointed with the CHMP opinion which will result in a delay to patients receiving an important new treatment option. We strongly believe that Avastin is a new treatment option for physicians within the EU which would bring hope to GBM patients and their families as it is today in the US and other countries,? said William M. Burns, CEO of Roche?s Pharmaceuticals Division. ?Relapsed glioblastoma is a rare condition and represents a very high unmet medical need. These patients deserve effective additional therapies to manage this devastating disease. We remain committed to bringing Avastin to patients with newly diagnosed GBM in Europe?.In May 2009 bevacizumab was granted accelerated approval for the treatment of GBM patients with progressive disease following prior therapy from the US Food and Drug Administration (FDA) based on data from the BRAIN study (AVF3708g) and an NCI study (NCI 06-C-0064E). Switzerland and ten other countries have already recognised the significant clinical benefits bevacizumab offers to GBM patients by giving approval.Continued research and explorationThe company continues to further explore the role of bevacizumab in GBM through various investigator-led studies. In addition, a large international, multicentre, randomised, double blind, phase III study (AVAGLIO) in over 900 patients with newly diagnosed GBM is currently underway with the aim of a global filing9. This study will investigate the efficacy and safety of treatment with bevacizumab combined with standard of care (temozolomide chemotherapy and radiotherapy) following surgery.In other cancersBevacizumab has shown survival benefits across several types of cancer. It is approved in Europe for the treatment of the advanced stages of four common types of cancer: colorectal cancer, breast cancer, non-small cell lung cancer (NSCLC) and kidney cancer. These types of cancer collectively cause over 2.5 million deaths each year8,9,10. Over half a million patients have been treated with bevacizumab so far.References1. Central Brain Tumor Registry of the United States (CBTRUS). Primary Brain Tumours in the United States Statistical Report.2. Stupp R et al. Ann Oncol 2007; 18 (supplement 2): ii69?ii70.3. Medscape. Recurrent Glioblastoma Multiforme: Definition of Recurrent GBM.4. Friedman HS, Prados MS, Wen PY, et al. Bevacizumab Alone and in Combination With Irinotecan in Recurrent Glioblastoma J Clin Oncol 2009; 31 August [Epub ahead of print as doi/10.1200/JCO.2008.19.8721].5. Decision Resources, Cancer Incidence in 5 Continents Version IX, CI5 IX, World Population Prospects, Central Brain Tumor Registry of the United States, National Swedish Brain Tumour Registry6. Vredenburgh, J. et al. ECCO 15 ESMO 34 2009; Abstract #8707.7. Chinot, O. et al. ECCO 15 ESMO 34 2009; Poster #468. Garcia M et al. Global Cancer Facts & Figures. Atlanta, GA: American Cancer Society, 20079. WHO Cancer Factsheet N?297 ? updated July 2008. Last accessed 24 March 2009 at 10. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005 Mar-Apr;55(2):74-10811. Takano S, Yoshii Y, Kondo S, Suzuki H, et al. Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res. 1996 May 1;56(9):2185-90. http://www.ncbi.nlm.nih.gov/pubmed/8616870
