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Brivanib Alaninate for Hepatocellular Cancer Brivanib alaninate for hepatocellular cancer 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 February 2012 Brivanib alaninate for hepatocellular cancer Target group • Hepatocellular cancer (HCC): advanced, not eligible for surgical or locoregional therapies, or progression following surgical or locoregional therapies. Technology description Brivanib alaninate (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 administered orally at 800mg once daily. Brivanib alaninate is in phase III clinical trials as an adjuvant treatment for metastatic colorectal cancer, and as a second line treatment for advanced 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 this patient group4,5. 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. Hepatocellular carcinoma (advanced and metastatic) – sorafenib (first line). 20103. • NICE interventional procedure guidance. Ex-vivo hepatic resection and reimplantation for liver cancer. 20096. • NICE interventional procedure guidance. Microwave ablation of hepatocellular carcinoma. 20077. • NICE interventional procedure guidance. Radiofrequency-assisted liver resection. February 20078. 9 • NICE interventional procedure guidance. Laparoscopic liver resection. 2005 . • NICE interventional procedure guidance. Radiofrequency ablation of hepatocellular carcinoma. July 200310. 2 February 2012 Clinical need and burden of disease Liver cancer is the 18th most commonly diagnosed cancer in UK, with around 3,594 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 rising 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 non-alcoholic steatohepatitis; diabetes; and obesityb. In England and Wales, 1,323 deaths due to HCC were registered in 201016. In 2010-2011 there were 3,333 admissions for HCC in England, resulting in 19,995 bed days and 4,557 finished consultant episodes17 (ICD10 C22.0). Existing comparators and treatments For the majority of patients treatment is palliative rather than curative. For intermediate stage disease, transarterial embolisation may improve survival, and for advanced HCC, sorafenib is the current standard of careb. 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. Efficacy and safety Trial NCT00858871, CA182-033, NCT00355238, CA182-006; adults; EUDRACT #2008-003533-24; adults; brivanib; phase II. brivanib vs sorafenib; phase III. Sponsor Bristol-Myers Squibb. Bristol-Myers Squibb. Status Ongoing. Complete. Source of Trial registry19,20. Publication21, trial registry22. information Location EU (inc UK), USA, Canada and other EU, USA and other countries. countries. Design Randomised, active-controlled. Uncontrolled, open label. Participants n=1,050 (planned); adults; HCC; n=55; adults; HCC; not suitable for and schedule advanced; not eligible for surgical curative surgery. and/or locoregional therapies or Brivanib, oral, 800mg once daily. progressive disease following surgical and/or locoregional therapies. Randomised to brivanib, oral, 800mg once daily, or sorafenib, oral, 400mg twice daily. Both arms also take placebo, oral, twice daily. Follow-up Active treatment period until disease Active treatment period until disease progression; follow-up until death. progression; follow-up until death. Primary Overall survival (OS). 6 month progression free survival outcome (PFS). a Expert communication. 3 February 2012 Secondary Time to progression (TTP); objective Tumour response rate; TTR; DR; OS; outcomes response rate (ORR); disease control DCR; FHSI-8c; safety and tolerability; rate (DCR)b; duration of response (DR); pharmacokinetics; pharmacodynamics. duration of disease control; time to response (TTR); safety; pharmacokinetics; exposure-response; symptomatic progression; health-related quality of life. Key results - 6 mth PFS, mWHO criteriad, 21.1% (95% CI 9.6-32.5); median PFS 2.7 mths (95% CI 1.4-3.0); DCR, 51%; partial response, 5.5%; stable disease 43.6%; time to partial response, 5-54.1 weeks; median TTP, 2.8 mths (95% CI 1.5-2.8); median OS, 10 mths (95% CI 6.8-15.2). Adverse - AEs >15% (%): fatigue, 45.5; effects (AEs) hypertension, 45.5; diarrhoea, 41.8; nausea, 38.2; anorexia 38.2; vomiting, 29.1; weight decrease, 29.1; upper abdominal pain, 18.2; dyspnoea, 18.2; headache, 18.2; dizziness, 18.2; peripheral oedema, 18.2; constipation 18.2. Expected Q4 2012 – Q1 2013. - reporting date Estimated cost and cost impact The cost of brivanib is not yet known. Sorafenib (Nexavar) at a dose of 400mg twice daily, costs £38,85323 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: Savings: Other: uncertain unit cost compared to alternative options b Complete response + partial response + stable disease c FHSI-8 – an 8 item symptom index derived from FACT-Hep (Functional Assessment of Cancer Therapy), a validated instrument for assessing quality of life in patients with hepatobiliary cancers. d Immune-related response criteria (IRRC) assessment. 4 February 2012 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. 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
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