Horizon Scanning Technology Briefing. Cetuximab (Erbitux) for metastatic colorectal cancer. National Horizon Scanning Centre.

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1 Horizon Scanning Technology Briefing National Horizon Scanning Centre Cetuximab (Erbitux) for metastatic colorectal cancer December 2006 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.

2 Cetuximab (Erbitux) for metastatic colorectal cancer Target group In combination with irinotecan as second line treatment for metastatic colorectal cancer after failure with 5-FU/FA and oxaliplatin (FOLFOX). In combination with irinotecan as third line treatment for metastatic colorectal cancer after 5-FU/FA in the first line and FOLFOX in the second line. Technology description Cetuximab (Erbitux) is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody which prevents the proliferation of cells by binding to EGFR and preventing autophosphorylation of the intracellular region 1. It is administered by intravenous infusion at an initial dose of 400mg/m 2 followed by a weekly dose of 250mg/m 2, in combination with irinotecan 350mg/m 2 every 3 weeks. Until trial results are obtained the length of treatment cannot be confirmed but the company estimate that in the 2 nd line setting therapy could last weeks, and 16 weeks in the 3 rd line setting. Cetuximab is currently licensed or in development for: Colorectal cancer Licensed for: metastatic EGFR expressing colorectal cancer in combination with irinotecan after failure of irinotecan-including cytotoxic therapy. In phase III development for: metastatic colorectal cancer first line therapy in combination with 5-FU/FA and irinotecan (FOLFIRI) or FOLFOX. Head and neck cancer Licensed for: locally advanced squamous cell cancer of head and neck (stages 3, 4a, 4b) in combination with radiotherapy. In development for: recurrent and/or metastatic cancer of head and neck. Non small cell lung cancer In phase III development for: 1 st line combination therapy for stage IIIb (with documented malignant pleural effusion) or stage IV non-small cell lung cancer. Pancreatic cancer In phase III development for: metastatic pancreatic cancer 1 st line and recurrent disease in combination with gemcitabine. Innovation and/or advantages By targeting EGFR cetuximab has a specific mechanism of action on malignant cells. Developer Merck Pharmaceuticals 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 Primary care e.g. used by GPs or practice nurses Emergency care e.g. paramedic services, trauma care NHS or Government priority area: Cancer Cardiovascular disease Children Dec

3 Diabetes Chronic conditions Mental health Older people Public health Renal disease Women s health None identified Relevant guidance NICE guidance on cancer services: improving outcomes in colorectal cancers, June NICE technology appraisals: Bevacizumab and cetuximab for advanced metastatic colorectal cancer (2 nd line and subsequent treatment post irinotecan failure). Guidance currently being appealed. Capecitabine and oxaliplatin for adjuvant treatment of stage III colon cancer (adjuvant). April Irinotecan, oxaliplatin and raltitrexed (review) for colorectal cancer. August Capecitabine and tegafur with uracil for metastatic colorectal cancer. May Irinotecan for the adjuvant treatment of colon cancer. Expected date of issue to be confirmed. Clinical need and burden of disease There were 30,515 new registrations for colorectal cancer in England and Wales in 2002 and 14,031 deaths in ,3. Estimates for the number of people presenting with metastatic disease range between 20-55% of new cases (6,103-16,783 patients) 4. Of those identified with early stage disease it is estimated 50% will develop advanced disease and distant metastases following surgery (15,260 patients). Metastatic colorectal disease has a five-year survival rate of 12%, median survival times of 5-6 months without treatment and less than 2 years with treatment 4,5. Existing comparators and treatments Current 1 st line therapies include 5-FU/FA a, FOLFOX, FOLFIRI and bevacizumab in combination with intravenous 5-FU/FA with or without irinotecan. Oral analogues of 5-FU (capecitabine and tegafur with uracil) may also be used instead of infusional 5-FU. Irinotecan may be used as second line treatment following FOLFOX failure and FOLFOX may be used as second line treatment following FOLFIRI failure. FOLFOX and irinotecan may be used as second line and subsequent treatment after first line failure of 5-FU/FA or oral therapy 4. Efficacy and safety Trial name or code EPIC 6, 7 Sponsor Status Location Design Participants in trial 2 nd Line after FOLFOX ImClone systems, Bristol-Myers Squibb, Merck KGaA Phase III, abstract Europe; Australia; Asia; USA Randomised, open label, active control. Target n=1300 EGFR positive metastatic colorectal cancer. Failed previous first line treatment with a fluopyrimidine and oxaliplatin based, non-irinotecan a Expert opinion suggests that 5-FU/FA is not used as a stand alone therapy by many UK centres Dec

4 containing regimen. National Horizon Scanning Centre Primary outcome Secondary outcomes Key results Expected reporting date Major adverse effects Arm A: cetuximab 400mg/m 2 week 1 followed by 250mg/m 2 weekly thereafter and irinotecan 350 mg/m 2 every 3 weeks. Arm B: irinotecan 350mg/m 2 every 3 weeks. Overall survival Progression free survival, response rate, duration of response, time to response, disease control rate, safety, quality of life and health economic resource utilization. Primary endpoint not met, interpretation of results ongoing. Secondary endpoints favour the cetuximab/irinotecan arm 8 Full results to be presented in 2007 Interim analysis of 783 patients: 2 grade 3, and 2 grade 4 severe infusion reactions. 59 deaths occurred within 30 days of last study therapy: 45 disease related, 5 study drug related, 6 other causes, 3 unknown etiology. Estimated cost and cost impact A 16-week course of cetuximab will cost approximately 11,000. A week course will cost approximately 16,500-19,000 for an average patient assuming wastage. Irinotecan costs 833 every 3 weeks. Potential or intended impact speculative Patients Reduced morbidity Quicker or more accurate diagnosis Reduced mortality or increased survival Earlier identification of disease Improved quality of life for patients and/or carers Services Increased use Service reorganisation required Staff or training required Decreased use e.g. shorter length of stay, reduced referrals Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment New costs: Savings: Increased costs: capital investment needed References Dec

5 1 Silvestri GA, Rivera MP. Targeted therapy for the treatment of advanced non-small cell lung cancer. Chest 2005; 128 (6): Cancer Research UK, Cancer Stats Incidence- UK, Cancer Research UK, Cancer Stats Mortality- UK, National Institute of Health and Clinical Excellence. Colorectal cancer (advanced)- bevacizumab and cetuximab appraisal consultation document Emergency Care Research Institute: evidence reports on emerging technologies (Target). Cetuximab (Erbitux) for metastatic colorectal cancer packerc&doc_id=8052. (accessed 30/05/06). 6 Abubakr Y, Eng C, Pautret V, Maurel J, Scheithauer W, Kroening H, Zubel A, Lutz M, Wong L, Sobrero A. Cetuximab plus irinotecan for metastatic colorectal cancer (mcrc): Safety analysis of 800 patients in a randomized phase III trial (EPIC). Journal of clinical oncology 2006:24;(18S) abstract Clinicaltrials.gov. Phase III study of irinotecan and cetuximab vs. irinotecan as second-line treatment in patients with metastatic, EGFR-positive colorectal cancer. accessed (20/11/06). 8 Merck KgaA. Survival data available from two randomized erbitux studies in metastatic colorectal cancer. Press release November c12d?OpenDocument.(accessed 01/12/06). The National Horizon Scanning Centre is funded by the Research and Development Division of the Department of Health, England The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0) Dec