Aflibercept (VEGF Trap) for advanced chemo-refractory epithelial ovarian cancer 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
Aflibercept (VEGF Trap) for advanced chemo-refractory epithelial ovarian cancer Target group Ovarian cancer advanced, third line monotherapy. Technology description Aflibercept (VEGF Trap) is a fusion protein that combines the constant region of a human IgG antibody with the ligand-binding portion of the vascular endothelial growth factor (VEGF). This new mode of action has a greater affinity for the VEGF ligand than anti-vegf monoclonal antibodies (reportedly around a 1000 times greater than bevacizumab). Aflibercept inhibits VEGF-induced signalling and VEGF-driven angiogenesis, and blocks placental growth factor, which also appears to play a role in angiogenesis. This reduces vascularisation of tumours, thereby inhibiting tumour growth. Aflibercept is administered as an intravenous infusion. Based on clinical trials the dose may be 2 or 4 mg/kg every 2 weeks. Aflibercept is also in clinical trials for: Second line treatment of non-small cell lung cancer (in combination with docetaxel) and colorectal cancer (in combination with folinic acid, 5-FU and irinotecan) licensing applications expected in 2010. First line treatment of pancreatic cancer (in combination with a gemcitabine-based regimen), and hormone-refractory metastatic prostate cancer - licensing applications expected 2011. Innovation and/or advantages Aflibercept s new mechanism of action may provide the potential for it to be a more powerful anti-angiogenesis agent than current options, prolonging stable disease in a group of patients with few therapeutic options. Developer Sanofi-Aventis 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: A licensing application is anticipated during 2008 and may be based on the results of the completed phase II trial. NHS or Government priority area: This topic is relevant to the NHS Cancer Plan Relevant guidance NICE clinical guideline in progress. Ovarian cancer - recognition and initial management (17 th wave). 2
NICE technology appraisal: o Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for the treatment of advanced ovarian cancer. 2005. Review expected February 2008 1. o Review of the clinical effectiveness and cost effectiveness of paclitaxel for ovarian cancer. 2003 2. Scottish Intercollegiate Guideline Network (SIGN). Epithelial ovarian cancer. 2003 3 recommended for review (2007). Clinical need and burden of disease Ovarian cancer is the fourth most common cause of cancer mortality in women and resulted in 3,939 deaths in England and Wales in 2005 4. The total number of new cases in registered in 2004 in England and Wales was approximately 5,070 5. Around 85% of cases occur in women over 50 years. Epithelial ovarian cancer, which involves the formation of malignant cells in the tissue covering the ovary accounts for around 85-90% of all ovarian cancers. The 5-year survival rate in 2000-2001 is estimated at 40% 6. Ovarian cancer is often asymptomatic in the early stages and over 75% of cases are diagnosed with advanced stage III or stage IV disease, around 3,800 cases per year. Between 55% and 75% of women whose tumours respond to first line therapy relapse within 2 years of completing treatment and studies suggest around 50% of patients will progress on second line treatment 7. On this basis, approximately 1,000 1,700 patients may be eligible for third line therapy. Existing comparators and treatments Surgery with either neoadjuvant or adjuvant chemotherapy. First line chemotherapy with platinum-based therapy alone or in combination with paclitaxel (where the platinum agent is either carboplatin or cisplatin). First line options may be repeated for second (and subsequent) treatments. New options may include single-agent paclitaxel, PLDH (pegylated liposomal doxorubicin hydrochloride), gemcitabine, doxorubicin or topotecan. Second line chemotherapy is palliative and aims to reduce symptoms and prolong survival. Ovarian tumours eventually develop multi-drug resistance. Efficacy and safety Trial name or code Aflibercept monotherapy - recurrent epithelial multi-resistant ovarian cancer; phase II 8 Aflibercept monotherapy advanced ovarian cancer with recurrent malignant ascites; phase II/III 9 Sponsor Sanofi-Aventis, Regeneron Sanofi-Aventis, Regeneron Status Conference abstract and presentation Ongoing Location USA, Europe USA Design Randomised, double-blind. Randomised, double-blind, placebocontrolled. Participants n=200; multi-resistant disease. Aflibercept administered i.v. (2 or 4 mg/kg) every 2 weeks. Average of 5 cycles received (range 1-15). n=54; multi-resistant disease. Aflibercept administered i.v. every 2 weeks. Follow-up Not known Not known Primary Objective response rate at 2 different Time to repeat paracentesis. outcome doses. Secondary Time to progression; progression free Ascites impact measure (patient 3
outcomes survival; overall survival; surrogate marker (CA-125) reduction; time to CA-125 progression; safety; quality of life (QoL) Key results Combined preliminary results in 162 patients (study remains blinded with regards to dose) showed partial response in 13 (8%); and stable disease in 77% at 4 weeks and 41% at 14 weeks. Of 23 with ascites, resolution occurred in 7, 13 remained stable. CA- 125 protein levels were reduced by >50% in 21 patients (13%). Expected Complete results expected mid 2008. reporting Adverse effects Most common grade 3/4 adverse events included hypertension (18%); proteinuria (7%) and headache (4%). 2 patients experienced bowel perforation (<1%), but recovered. questionnaire); 60-day frequency of paracentesis; safety, tolerability; tumour assessments; QoL - Not known - Estimated cost and cost impact The cost of aflibercept is currently unknown. Any costs will be additional to currently available chemotherapy regimens. Potential or intended impact speculative Patients Reduced morbidity Reduced mortality or increased survival Quicker, earlier or more accurate Other: diagnosis or identification of disease Improved quality of life for patients and/or carers Non identified Services Increased use additional intravenous therapy 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 Increased costs: capital investment needed New costs additional therapy Savings: Other: References 1 National Institute for Health and Clinical Excellence. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for the treatment of advanced ovarian cancer. Technology Appraisal 91. London: NICE, May 2005. 2 National Institute or Health and Clinical Excellence. Review of the clinical effectiveness and cost effectiveness of paclitaxel for ovarian cancer. Technology Appraisal 55. London: NICE, January 2003. 3 SIGN, Epithelial ovarian cancer. Guideline no.75, October 2003. 4 Cancer Research UK. UK ovarian cancer mortality statistics. Accessed 3/12/2007. Available online at Hhttp://info.cancerresearchuk.org/cancerstats/types/ovary/mortality/H. 5 Cancer Research UK. UK ovarian cancer incidence statistics. Accessed 3/12/2007. Available online at Hhttp://info.cancerresearchuk.org/cancerstats/types/ovary/incidence/H. 4
6 Cancer Research UK. UK ovarian cancer survival statistics. Accessed 3/12/2007. Available online at Hhttp://info.cancerresearchuk.org/cancerstats/types/ovary/survival/H. 7 Gordon AN, Fleagle JT, Guthrie D et al. Pegylated liposomal doxorubicin prolongs survival compared to topotecan as second-line treatment in women with platinum-sensitive ovarian cancer. Evidence-based oncology 2002; 3: 21-23. 8 Tew WP, Colombo N, Ray-Coquard I et al. VEGF-Trap for patients with recurrent platinum resistant epithelial ovarian cancer (EOC). Preliminary results of a randomised, multicentre phase II study. J Clin Oncol. 2007 ASCO Annual Meeting Proceedings Part I. Vol 25 (18S), 2007. Abstract number 5508. Accompanying oral presentation given at 43 rd ASCO annual meeting, Chicago. Accessed 11/12/2007. Available online at: Hhttp://media.asco.org/media/vm2007/10012/Lectures/2738/PPT/1.jpgH. 9 Clinicaltrials.gov. Study of the effect of intravenous AVE0005 (VEGF Trap) in advanced ovarian cancer patients with recurrent symptomatic malignant ascites. Accessed 11/12/2007. Available online at: Hhttp://clinicaltrials.gov/ct2/show/NCT00327444?term=Aflibercept+ovarian&rank=4H. 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 5