National Horizon Scanning Centre. Erlotinib (Tarceva) in combination with bevacizumab for advanced or metastatic non-small cell lung cancer

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1 Erlotinib (Tarceva) in combination with bevacizumab for advanced or metastatic non-small cell lung cancer 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

2 Erlotinib (Tarceva) in combination with bevacizumab for advanced or metastatic non-small cell lung cancer Target group Non-small cell lung cancer (NSCLC) - locally advanced or metastatic (stage IIIB and IV) disease, in combination with bevacizumab (Avastin): second-line therapy after failure of standard first-line therapy; maintenance therapy after standard first-line therapy. Technology description Erlotinib (Tarceva, CP , OSI-774, R-1415) is an orally-active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is used as a second-line monotherapy (150mg daily) for patients with locally advanced or metastatic NSCLC. Bevacizumab (Avastin) is an intravenous humanised anti-vascular endothelial growth factor (VEGF) monoclonal antibody, which inhibits VEGF-induced signalling and partially inhibits VEGF-driven angiogenesis. It is used in combination with platinumbased agents as first-line therapy, and administered as 7.5mg/kg or 15mg/kg of body weight once every three weeks by intravenous (iv) infusion. Innovation and/or advantages Combining the anti-egfr agent erlotinib with the anti-angiogenic agent bevacizumab may provide an alternative to conventional cytotoxic chemotherapy, offering improved efficacy and reduced toxicity. Erlotinib is orally bioavailable, and better tolerated than the standard second-line chemotherapy agent docetaxel. Developer Roche Products Ltd. Place of use Home care erlotinib Secondary care - non-specialist hospital capable of chemotherapy - bevacizumab General public e.g. over the counter Community or residential care e.g. district nurses, physio Tertiary care bevacizumab (iv infusion every 21 days) 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: In phase III clinical trials. NHS or Government priority area: This topic is relevant to the NHS Cancer Plan. Relevant guidance NICE clinical guideline Lung Cancer: the diagnosis and treatment of lung cancer (expected review date February 2009) 1. NICE technology appraisals Pemetrexed for the treatment of non-small cell lung cancer

3 Docetaxel, paclitaxel, gemcitabine and vinorelbine for the treatment of non-small cell lung cancer (now replaced by NICE Clinical Guideline on Lung Cancer, 2005) 3. Bevacizumab for non-small cell lung cancer. Expected January Erlotinib for advanced non-small cell lung cancer. Expected April Scottish Intercollegiate Guidelines Network (SIGN): Management of patients with lung cancer European Society for Medical Oncology (ESMO): Minimum clinical recommendations for the diagnosis, treatment and follow-up of non-small cell lung cancer US National Comprehensive Cancer Network (NCCN): clinical practice guideline on non-small cell lung cancer Clinical need and burden of disease Lung cancer is the most common cause of death in the UK. In England and Wales there were 32,715 new cases diagnosed in 2004, with 28,632 deaths registered in 2005 (around 54 deaths per 100,000 of population) 9. In England and Wales lung cancer has a one-year survival rate of 25% and a five-year survival rate of 7% 10. NSCLC accounts for approximately 80% of all lung cancers. Approximately 75% of newly diagnosed patients already have advanced (stage III or IV) disease 11 (around 24,536 patients in England and Wales), with a five-year survival rate of less than 1% 12. NICE estimates that around 25% of patients with advanced NSCLC receive first-line chemotherapy 13. Around 30-40% of these patients may subsequently become candidates for second-line therapy (approximately 1,840-2,454 patients) 14. Existing comparators and treatments Treatment options for stage IIIB or IV NSCLC include radiation therapy, chemotherapy with radiation therapy, and chemotherapy alone. Chemotherapy may be recommended for patients with non-resectable stage III or IV disease provided they have a good performance status. Current NICE guidance recommends that first-line chemotherapy should include a combination of a platinum drug (cisplatin or carboplatin) and a single third generation drug, such as docetaxel, gemcitabine, pacitaxel or vinorelbine. Second-line therapy options include: docetaxel (Taxotere) monotherapy. erlotinib (Tarceva) monotherapy licensed and NICE guidance expected April pemetrexed (Alimta) licensed but not currently recommended by NICE. bevacizumab (Avastin) licensed for first-line combination therapy; NICE guidance expected January gefitinib (Iressa) experimental use in clinical trials, not in current practice (unlicensed). Efficacy and safety Trial name or code BeTa/NCT ; second-line. Phase III NCT ; secondline. Phase II ATLAS/NCT ; maintenance. Phase III Sponsor Genentech Genentech Genentech Status In progress Published 15 In progress Location Multicentre Multicentre USA 3

4 Design Randomised, placebo- controlled, double-blind. Randomised. Randomised, placebo- controlled, double-blind. Participants N=650; failed first-line N=120; failed platinum- N=1,150; advanced chemotherapy or chemoradiotherapy. Randomised to erlotinib + bevacizumab, or erlotinib alone. or pemetrexed) based regimen. Randomised to bevacizumab + erlotinib (B+E); bevacizumab + chemotherapy (docetaxel (B+chemo); NSCLC (stage IIIB/IV) or non-progressive disease, after first-line chemotherapy with bevacizumab. Randomised to erlotinib + bevacizumab or bevacizumab alone. or chemotherapy alone (chemo). Primary Overall survival Progression-free survival Progression-free survival outcome Secondary Progression-free survival Overall survival (OS) Adverse events, outcomes (PFS), objective response, discontinuations, overall duration of response. survival. Results Expected Q No significant difference Expected Q 2009 in progression or death relative to chemo alone. Median OS: 13.7, 12.6 and 8.6 months for B+E, B+chemo, and chemo respectively; one-year survival was 57.4%, 53.8%, and 33.1% respectively. Adverse - Grade 5 haemorrhage with - effects bevacizumab 5.1%; consistent with previous trials. Estimated cost and cost impact Erlotinib costs around 6,800 a for a course lasting 125 days (treatment duration taken from second-line studies). The intended duration of treatment for maintenance use is not known. Potential or intended impact speculative Patients Reduced morbidity Reduced mortality or increased survival Improved quality of life for patients and/or carers - fewer adverse events, e.g. neutropenia Quicker, earlier or more accurate None identified diagnosis or identification of disease Services Increased use capacity issues Service reorganisation required Staff or training required in relation to administration of intravenous therapies. Decreased use lower toxicity compared to standard treatment None identified a British National Formulary edition 53, March

5 Costs Increased unit cost compared to alternative New costs: Increased costs: more patients coming for treatment Savings: Increased costs: capital investment needed References 1 National Institute for Health and Clinical Excellence. Lung Cancer: The diagnosis and treatment of lung cancer. Clinical Guideline 24, February National Institute for Health and Clinical Excellence. Pemetrexed for the treatment of non-small cell lung cancer. Technology Appraisal 124, August National Institute for Health and Clinical Excellence. Docetaxel, paclitaxel, gemcitabine and vinorelbine for the treatment of non-small cell lung cancer. Technology Appraisal 26, 2001 (now replaced by NICE Clinical Guideline 24). 4 National Institute for Health and Clinical Excellence. Bevacizumab for the treatment of non-small cell lung cancer.. Technology Appraisal in development - publication expected January National Institute for Health and Clinical Excellence. Erlotinib for the treatment of advanced non-small cell lung cancer.. Technology Appraisal in development - publication expected April Scottish Intercollegiate Guidelines Network (SIGN): Management of patients with lung cancer, Guideline 80, February ESMO: Minimum clinical recommendations for the diagnosis, treatment and follow-up of non-small cell lung cancer (NSCLC). Annals of Oncol 2005; 16 (1): National Comprehensive Cancer Network (NCCN): clinical practice guideline on non-small cell lung cancer, September Cancer Research UK, Cancer Stats Lung cancer and smoking UK, July Coleman M, Rachet B, Woods L et al. Trends in socio-economic inequalities in cancer survival in England and Wales up to 2001, British Journal of Cancer 2004; 90(7): Liverpool Reviews and Implementation Group, ERG Report Pemetrexed for the treatment of relapsed nonsmall cell lung cancer, September 2006, London: National Institute for Clinical Excellence 12 National Collaborating Centre for Acute Care, The diagnosis and treatment of lung cancer: methods, evidence and guidance; February 2005, London: National Collaborating Centre for Acute Care. 13 National Institute for Clinical Excellence (NICE) technology appraisal in development: Bevacizumab for the treatment of non small cell lung cancer final scoping document April 2007, accessed online 20 Nov 2007 at 14 Hu C, Davies AM, Lara PN et al. Second-line treatment for advanced-stage non-small cell lung cancer: current and future options. Clinical Lung Cancer 2006; 7(4): S Herbst RS, O Neill VJ, Fehrenbacher L et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung cancer. J Clin Oncol 2007; 25 (30): 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, D epartment of Public Health and Epidemiology University of B irmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0)