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Brivanib for Hepatocellular Carcinoma – Second Line Brivanib for hepatocellular carcinoma – second line December 2011 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 December 2011 Brivanib for hepatocellular carcinoma – second line Target group • Hepatocellular carcinoma (HCC): advanced – second line; after failure of or intolerance to sorafenib. Technology description Brivanib alaninate (Brivanib; BMS-540215; BMS-582664) is the orally available pro- drug of brivanib, a selective dual inhibitor of vascular endothelial growth factor (VEGF) receptor 2 and fibroblast growth factor (FGF) receptor 1. It is thought that VEGF signalling is required for the initiation of tumour angiogenesis and FGF signalling contributes to its maintenance in HCC, a highly vascular tumour1,2. Elevated VEGF is associated with postoperative recurrence and poor prognosis in HCC2. VEGF receptor inhibitors, such as sorafenib, reduce primary tumour growth, but may promote tumour invasiveness and metastasis associated with up regulation of pro-angiogenic ligands, including the FGF family1,3,4. Concomitant blockade of FGF and VEGF signalling could therefore limit the re-induction of angiogenesis and consequent tumour regrowth that typifies the response to anti-VEGF agents5. Brivanib alaninate is intended as a second line therapy for the treatment of HCC following failure or intolerance to sorafenib. It will be administered orally at 800mg daily. Brivanib alaninate is in phase III clinical trials as an adjuvant treatment for metastatic colorectal cancer, and as a first line and adjuvant treatment for HCC. It is also in a phase II clinical trial as monotherapy for the treatment of solid tumours (including gastric, oesophageal, lung, pancreatic, bladder and sarcoma). Innovation and/or advantages Treatment with VEGF receptor blocker monotherapy can produce an initial anti-tumour response, though overall responses are modest. If licensed, the dual inhibition of VEGF and FGF by brivanib has the potential to improve outcomes for those with treatment- resistant HCC4,5. Developer Bristol-Myers Squibb. 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. Sorafenib for the treatment of advanced hepatocellular carcinoma. May 20103. • NICE interventional procedure guidance. Ex-vivo hepatic resection and reimplantation for liver cancer. April 20096. • NICE interventional procedure guidance. Microwave ablation of hepatocellular carcinoma. March 20077. • NICE interventional procedure guidance. Radiofrequency-assisted liver resection. February 20078. 9 • NICE interventional procedure guidance. Laparoscopic liver resection. July 2005 . 2 December 2011 • NICE interventional procedure guidance. Radiofrequency ablation of hepatocellular carcinoma. July 200310. Clinical need and burden of disease Liver cancer is the 18th most commonly diagnosed cancer in UK, with around 3,181 new cases diagnosed in 200811. HCC is the main type of primary liver cancer, accounting for about 85% of cases12. Most cases of HCC are secondary to either a viral infection (hepatitis B or C) or cirrhosis13. The incidence of HCC has increased in recent years as a result of the prevalence of infection with hepatitis C virus14. Unlike the majority of cancers, HCC has very well-defined risk factors, with 80% of cases developing on the background of cirrhosis15. Approximately 40-50% of HCCs in Europe can be attributed to excessive alcohol consumptiona. Other risk factors include insulin resistance associated with the non-alcoholic fatty liver disease, non-alcoholic steatohepatitis; diabetes; and obesityb. In England and Wales, 1,323 deaths due to HCC were registered in 201016. In 2009-2010 there were 2,859 admissions for HCC in England, resulting in 19,491 bed days and 3,916 finished consultant episodes17 (ICD10 C22.0). Existing comparators and treatments The only potentially curative options for HCC are surgery or ablation in selected patients: • Hepatic resection - the treatment of choice in non-cirrhotic patients or patients with Child’s grade A cirrhosis, applicable in <18% of cases18,b. • Liver transplantation - limited by the shortage of cadaveric donors, applicable in only around 5% of patients9. • Radiofrequency ablation for solitary tumours less than 2cm appears to have equivalent outcome to surgical resectionb. For the majority of patients treatment is palliative rather than curative. For intermediate stage disease, transarterial embolisation may improve survivalb. For advanced HCC sorafenib is the only drug that has been shown to improve survival and is the current standard of careb. Efficacy and safety Trial BRISK, NCT00825955; phase III. BRISK-APS, NCT01108705; phase III. Sponsor Bristol-Myers Squibb. Bristol-Myers Squibb. Status Ongoing. Ongoing. Source of Trial registry19, manufacturer. Trial registry20, manufacturer. information Location EU, USA, Canada and other China, Republic of Korea, Singapore countries. and Taiwan. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants and n=414 (planned); adults; HCC; n=252 (planned); adults; asian ethnic schedule advanced; previously received ≥14 group; HCC; advanced; previously days of sorafenib treatment. received ≥14 days of sorafenib Randomised to brivanib 800mg or treatment. placebo, administered orally, once Randomised to brivanib 800mg or daily until disease progression or placebo, administered orally, once daily toxicity. until disease progression or toxicity. a Expert opinion. 3 December 2011 Follow-up 6 weekly scans until progression, and Active treatment, then follow up until 6 weekly survival follow-up until death. death. Primary outcome Overall survival (OS). OS. Secondary Time to progression using modified Time to progression using modified outcomes RECISTb for HCC criteria; objective RECIST for HCC criteria; ORR and response rate (ORR) and disease DCR using modified RECIST for HCC control rate (DCR) using modified criteria; duration of response, duration RECIST for HCC criteria; duration of disease control and time to response; of response, duration of disease adverse events; laboratory evaluations; control and time to response; adverse physical examination; ECG results. events. Expected reporting December 2011. September 2014. date Estimated cost and cost impact The cost of brivanib is not yet known. There are no licensed comparators. Sorafenib (Nexavar) for a dose of 400mg twice daily costs £38,85321 per year. Claimed or potential impact – speculative Patients Reduced mortality or increased Reduction in associated morbidity Quicker, earlier or more accurate length of survival or Improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified Services Increased use Service organisation Staff requirements Decreased use Other: None identified Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Additional treatment Savings: Other: option. Other issues Clinical uncertainty or other research question identified: None identified References 1 Allen E, Walters IB, and Hanahan D. Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clinical Cancer Research 2011;17(16); 5299–310. 2 Huynh H. Molecularly targeted therapy in hepatocellular carcinoma. Biochemical Pharmacology 2010;80(5): 550-560. 3 National Institute for Health and Clinical Excellence. Sorafenib for the treatment of advanced hepatocellular carcinoma. Technology appraisal TA189. London: NICE; May 2010. 4 Finn RS. Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now? Clinical Cancer Research 2010;16(2):390–397. 5 Syed S, Clemens PL, Lathers D et al. Lack of effect of brivanib on the pharmacokinetics of midazolam, a cyp3a4 substrate, administered intravenously and orally in healthy participants. Journal of Clinical Pharmacology 2011. DOI: 10.1177/0091270011407495. b Response evaluation criteria in solid tumors. 4 December 2011 http://jcp.sagepub.com/content/early/2011/06/09/0091270011407495.full.pdf+html 6 National Institute for Health and Clinical Excellence. Ex-vivo hepatic resection and reimplantation for liver cancer IPG298. London: NICE; April 2009. 7 National Institute for Health and Clinical Excellence. Microwave ablation of hepatocellular carcinoma IPG214. London: NICE; March 2007. 8 National Institute for Health and Clinical Excellence. Radiofrequency-assisted liver resection IPG211. London: NICE; February 2007. 9 National Institute for Health and Clinical Excellence. Laparoscopic liver resection IPG135. London: NICE; July 2005. 10National Institute for Health and Clinical Excellence. Radiofrequency ablation of hepatocellular carcinoma IPG002. London: NICE; July 2003. 11Cancer Research UK. Liver Cancer Statistics. http://info.cancerresearchuk.org/cancerstats/types/liver/incidence/ Accessed 23 May 2011. 12Macmillan Cancer Support
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