Bevacizumab (Avastin) in combination with non-taxanes for metastatic breast cancer - first line therapy December 2007 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
Bevacizumab (Avastin) in combination with non-taxanes for metastatic breast cancer - first line therapy Target group Breast cancer - metastatic (stage IV), first line in combination with non-taxane chemotherapy 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 a 10mg/kg short intravenous infusion every 2 weeks, or as a 15mg/kg infusion every 3 weeks until disease progression (in excess of 9 months). Non-taxane chemotherapy combinations include anthracycline-based (doxorubicin or epirubicin) regimens or capecitabine (Xeloda). Bevacizumab is currently licensed for: Metastatic breast cancer: first line treatment in combination with paclitaxel. Metastatic colorectal cancer: in combination with cytotoxic chemotherapy. Non-small cell lung cancer (unresectable advanced, metastatic or recurrent): first line treatment in combination with 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 in this patient group. It would also provide another treatment option for people with metastatic breast cancer. Developer Roche Products Ltd. Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist hospital General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care e.g. highly specialist services or hospital Other: Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care Availability, launch or marketing dates, and licensing plans: Bevaciumab in combination with non-taxanes is in phase III clinical trials for first line therapy for metastatic breast cancer. NHS or Government priority area: This topic is relevant to the NHS Cancer Plan Relevant guidance NICE clinical guidelines in progress (due January 2009): o Advanced breast cancer diagnosis and treatment 2
o Early breast cancer diagnosis and treatment SIGN clinical guideline. Management of breast cancer in women, 2005 1. NICE cancer service guidance - Improving outcomes in breast cancer, 2002 2. NICE Technology Appraisals (in development) Bevacizumab for the treatment of advanced or metastatic breast cancer (with taxane-based chemotherapy). Expected publication date July 2008. Lapatinib for the treatment of advanced or metastatic breast cancer. Publication date to be announced. NICE Technology Appraisals (published) Advanced breast cancer: trastuzumab (2002 3 ), taxanes (docetaxel and paclitaxel, 2001 4 ), vinorelbine (2002 5 ), gemcitabine (2007 6 ) and capecitabine (2003 7 ). Early stage breast cancer: adjuvant hormonal therapies (2006 8 ), and for adjuvant treatment - trastuzumab (2006 9 ), docetaxel (2006 10 ) and paclitaxel (2006 11 ). Clinical need and burden of disease Breast cancer is the most common malignancy affecting women in the UK. There were 39,301 women newly diagnosed with breast cancer in England and Wales during 2004 12 and in 2005 there were 10,969 deaths, a rate of 40 deaths per 100,000 females 13. Between 16% and 20% of women (an estimated 6,288 to 7,860 women) presenting with breast cancer have advanced disease with distant metastases 3, and in 2002 NICE estimated that around 50% of those presenting with early or localised breast cancer will eventually develop metastatic breast cancer 3. Existing comparators and treatments The role of current treatments for advanced and metastatic breast cancer is to palliate symptoms, prolong survival and maintain a good quality of life. The choice of treatment is based on previous therapy, oestrogen receptor status, HER2 status and the extent of the disease. Current options include: First line systemic therapy for oestrogen receptor-negative disease is chemotherapy (usually an anthracycline based regimen a or a combination of cyclophosphamide, methotrexate and fluorouracil). Hormone manipulation therapy for oestrogen receptor positive tumours. Following disease progression on an anthracycline, other chemotherapy options include single-agent taxanes, capecitabine (in combination with docetaxel or as monotherapy), bevacizumab (in combination with paclitaxel), vinorelbine and gemcitabine in combination with paclitaxel. Trastuzumab in combination with taxanes is given to those with HER2+ metastatic disease. It may also be given on its own in women with advanced breast cancer who have already received at least two courses of chemotherapy 14. A large proportion of women who develop metastatic breast cancer may be unsuitable for anthracycline therapy due to the risk of cumulative cardiotoxicity from the use of these agents in the adjuvant setting. a Anthracycline based regimens include AC (doxorubicin and cyclophosphamide), EC (epirubicin and cyclophosphamide), CAF (cyclophosphamide, doxorubicin and fluorouracil), FEC (fluorouracil, epirubicin and cyclophosphamide) 3
Efficacy and safety Trial name or code XCALIBr: Bevacizumab + capecitabine first line; phase II 15 RIBBON 1 (AVF3694g) Bevacizumab + chemotherapy first line; phase III 16 Sponsor Roche, Genentech Roche, Genentech Status Conference abstract and presentation Ongoing Location USA Europe (incl UK),USA Design Single-arm Randomised, placebo-controlled Participants in trial Follow-up Primary outcome Secondary outcomes n=106; previously untreated metastatic breast cancer (HER2- negative). Received capecitabine 1000mg/m 2 twice daily on days 1-14 (28 doses) and bevacizumab 15mg/kg on day 1. Treatment repeated every 21 days until progression. Median follow up 12.9 months (range 0.5-20.7) Time to Progression (TTP) Overall survival (OS); overall response rate (ORR), median response rate; response duration, time to failure. Key results Average no. cycles received 6.8. Median TTP 5.7 months (4.9-8.4) in 106 intent-to-treat patients. Oestrogen-receptor positive subgroup had median delay of 8.9 months. Clinical benefit observed in 81.4% - ORR = 38.5% (complete response =5.5%; partial response =33.0%); stable disease in 42.9%. 84 pts alive at study end. Median OS 16+ months (95% CI: 12.9 - not reached). Expected reporting Adverse effects Majority of adverse events (AEs) were mild or moderate. Most common grade 3 AEs were hand-foot syndrome (13%) and pain (10%); grade 4 pulmonary embolism occurred in 4%. Of 24 deaths, 2 were treatment-related. n=1200; previously untreated metastatic breast cancer (HER2-negative). Received bevacizumab (15mg/kg every 3 weeks) in combination with any one of 3 chemotherapy agents: taxanes, anthracyclines, or capecitabine vs. chemotherapy alone. Progression free survival (PFS) Objective response; one-year survival rate; OS. - Patient recruitment completed Q2 2007. Efficacy data anticipated Q3 2008. - Estimated cost and cost impact For an average person of 67.5kg, the cost of a dose of bevacizumab will be approximately 1,650 at 10mg/kg, or 2,570 at 15mg/kg (assuming wastage) b. The estimated minimum 9-month treatment course would cost in the region of 33,000 c. This will be in addition to the cost of standard non-taxane chemotherapy regimens. b Costs from BNF 54. September 2007. c Based on calendar weeks 4
Bevacizumab will be administered during the same hospital visit as the other chemotherapy drugs in the combined regimen. Potential or intended impact speculative Patients Reduced morbidity Quicker, earlier or more accurate diagnosis or identification of disease Reduced mortality or increased survival Other: Improved quality of life for patients and/or carers Non identified Services Increased use Service reorganisation required Staff or training required Decreased use Other: Non identified Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment New costs: additional therapy Savings: Other: Increased costs: capital investment needed References 1 Management of breast cancer in women. Scottish Intercollegiate Guideline Network. Guideline 84, December 2005. 2 Improving outcomes in breast cancer. Cancer service guidance. National Institute for Health and Clinical Excellence. August 2002. 3 National Institute for Health and Clinical Excellence. Guidance on the use of trastuzumab for advanced breast cancer: The clinical effectiveness and cost effectiveness of trastuzumab for breast cancer, March 2002; Technology Appraisal Guidance number 34. 4 National Institute for Health and Clinical Excellence. Guidance on the use of taxanes for advanced breast cancer: Taxanes for the treatment of breast cancer, September 2001; Technology Appraisal Guidance number 30. 5 National Institute for Health and Clinical Excellence. Guidance on the use of vinorelbine for advanced breast cancer: The clinical effectiveness and cost effectiveness of vinorelbine for breast cancer, December 2002; Technology Appraisal Guidance number 54. 6 National Institute for Health and Clinical Excellence. Gemcitabine for the treatment of metastatic breast cancer, January 2007. Technology Appraisal Guidance number 116. 7 National Institute for Health and Clinical Excellence. Guidance on the use of capecitabine for advanced breast cancer: The clinical effectiveness and cost effectiveness of capecitabine for breast cancer, May 2003; Technology Appraisal Guidance number 62. 8 National Institute for Health and Clinical Excellence. Guidance on the use of hormonal treatments for early stage breast cancer: Hormonal therapies for the adjuvant treatment of early oestrogen-receptor-positive breast cancer, November 2006, Technology Appraisal Guidance number 112. 9 National Institute for Health and Clinical Excellence. Guidance on the use of trastuzumab for early-stage breast cancer: Trastuzumab for the adjuvant treatment of early-stage HER2-positive breast cancer, August 2006; Technology Appraisal Guidance number 107. 10 National Institute for Health and Clinical Excellence. Docetaxel for the adjuvant treatment of early nodepositive breast cancer, September 2006. Technology Appraisal Guidance number 109. 11 National Institute for Health and Clinical Excellence. Paclitaxel for the adjuvant treatment of early nodepositive breast cancer, September 2006. Technology Appraisal Guidance number 108. 12 Cancer Research UK. UK breast cancer incidence statistics. Accessed 15/11/2007. Available online at: Hhttp://info.cancerresearchuk.org/cancerstats/types/breast/incidence/H. 13 Cancer Research UK. UK breast cancer mortality statistics. Accessed 15/11/2007. Available online at: Hhttp://info.cancerresearchuk.org/cancerstats/types/breast/mortality/H. 14 Cancerbackup. Accessed 15/11/2007. Hhttp://www.cancerbackup.org.uk/cancertype/breast/treatment/herceptinH. 5
15 Sledge, G. Miller, K. Moisa, C. Gradishar, W. Safety and efficacy of capecitabine plus bevacizumab as firstline in metastatic breast cancer. J Clin Oncol. 2007 ASCO Annual Meeting Proceedings Part I. 2007; Vol 25;18S (abstract 1013). Accompanying oral presentation given at 43 rd ASCO annual meeting, Chicago. Accessed 27/11/2007. Available online at: Hhttp://media.asco.org/media/vm2007/10002/Lectures/5681/PPT/4.jpgH. 16 ClinicalTrials.gov. Efficacy and safety of bevacizumab in combination with chemotherapy in untreated metastatic breast cancer (RIBBON 1). Accessed 22/11/2007. Available online at: Hhttp://clinicaltrials.gov/ct/show/NCT00262067H. 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)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon 6