Horizon Scanning Technology Summary National Horizon Scanning Centre Temozolomide (Temodal) for advanced metastatic melanoma April 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. National Horizon Scanning Centre News on emerging technologies in healthcare Temozolomide (Temodal®) for advanced metastatic melanoma Target group • Palliative treatment for patients with advanced (stage IV) metastatic melanoma. Technology description Temozolomide (TMZ, Temodal, Temodar, CCRG 81045) is an oral cytotoxic alkylating agent which inhibits DNA replication in tumour cells, and is the lead in a class of compounds called imidazotetrazines. It is an analogue of the standard chemotherapy agent dacarbazine. Temozolomide is in phase III development for the palliative treatment of advanced metastatic melanoma, using in trials an administration regime of 150 mg/m2 given orally once daily on days 1-7, 15-21 and 29-35 per six week cycle. It is already approved for different types of brain cancer (including glioblastoma multiforme and anaplastic astrocytoma) in Europe and North America. Innovation and/or advantages Advanced melanoma is currently incurable, and new palliative treatments that offer improved tolerability and/or ease of use may be desirable. Temozolomide’s oral formulation will enable out-patient treatment, and may offer significant quality of life benefits over current options. Developer Schering-Plough Ltd. Place of use Home care e.g. home dialysis Secondary care e.g. general, nonspecialist 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: Temozolomide for stage IV metastatic melanoma is currently in clinical trials in Europe and pre-registration in the USA. NHS or Government priority area: Cardiovascular disease ; Cancer Diabetes Older people Long term neurological conditions Public health Children Mental health Renal disease Relevant guidance • NICE Cancer Service Guidance: improving outcomes for people with skin tumours including melanoma, 2006.1 • NICE Cancer Service Guidance: improving supportive and palliative care for adults with cancer, 2004.2 • Scottish Intercollegiate Guidelines Network (SIGN): National clinical guideline on cutaneous melanoma, 20033 (updated 2004): commented that for stage IV disease, temozolomide had equivalent efficacy and better central nervous system penetration than dacarbazine. April 2007 2 National Horizon Scanning Centre News on emerging technologies in healthcare • British Association of Dermatologists and the Melanoma Study Group: UK Guidelines for the management of cutaneous melanoma, 2002.4 • Canadian clinical practice guideline (for the Program in Evidence-Based Care and Cancer Care Ontario): temozolomide for the treatment of metastatic melanoma, 2006.5 Clinical need and burden of disease There were 7,363 new cases of malignant melanoma registered in England in 2004, and 1,622 deaths in England and Wales in 20056. The prognosis for patients with advanced (stage IV) disease is extremely poor, with a median survival time of approximately 6-9 months,7 and a 5-year survival rate of around 5-6%.8,9 Experts estimated the potential UK target group for temozolomide at 1,400-1,600 patients per year. The company estimates an eligible patients population of around 1,700 patients per year in the UK. Existing comparators and treatments • Single-agent chemotherapy with dacarbazine (DTIC), an alkylating agent administered intravenously. A 2007 Cochrane review10 found that cytotoxic alternatives to DTIC, including temozolomide, cisplatin and carboplatin, vinca alkaloids, taxanes and nitrosoureas, had not been shown to improve on standard chemotherapy with DTIC. Combination chemotherapies had also failed to demonstrate any significant benefit, except for a small increase in response rates.11 Chemoimmunotherapy (e.g. DTIC combined with interleukin-2 or interferon) was not found to prolong survival compared to chemotherapy alone, and a short-term increase in clinical response was associated with a higher rate of serious adverse events. Efficacy and safety Trial name Extended schedule, TMZ vs DTIC in stage IV metastatic melanoma (EORTC 18032/NCT00101218) Sponsor European Organisation for Research and Treatment (EORTC), Schering-Plough Status Published.8 In progress - enrolment to be completed in May 2007. Location Multicentre. Multicentre. Phase III randomised open label study. Design Phase III randomised open-label study. Arm A: oral TMZ 200 mg/m2 per day Arm A: oral TMZ 150 mg/m2 once daily for 5 days every 28 days, repeated in the on days 1-7, 15-21, and 29-35. absence of disease progression or Treatment repeats every 42 days. Each 6 toxicity (n=156). week period=1 cycle; 3 cycles over 4.5 months. Arm B: 30-minute intravenous infusion of DTIC 250 mg/m2 once per day for 5 Arm B: DTIC 1,000 mg/m2 days every 21 days (n=149). intravenously on day 1, and repeated Up to 12 cycles of treatment (doses every 21 days (=1 cycle); up to 6 cycles reduced in the event of grade 3 or 4 over 4.5 months. toxicity). Treatments A and B continue in the absence of disease progression or unacceptable toxicity. Participants in N=305 patients with surgically incurable N=880 patients with advanced (stage IV) April 2007 Temozolomide (TMZ) vs dacarbazine (DTIC) in advanced metastatic malignant melanoma (195-018) Schering-Plough Ltd. 3 National Horizon Scanning Centre News on emerging technologies in healthcare trial or unresectable metastatic melanoma. Follow-up Primary outcome Secondary outcomes Until death. Overall survival. Results Progression-free survival (PFS), healthrelated quality of life (HQoL), response rates, pharmacokinetics, safety and tolerability. Analysis by intention-to-treat. Median PFS time was significantly longer in the TMZ group (1.9 months) than the DTIC group (1.5 months); hazard ratio 1.37 (p=0.012, 95% CI 1.07-1.75). Median overall survival time. TMZ was equivalent to DTIC: 7.7 months for the TMZ group and 6.4 months for DTIC, with a hazard ratio of 1.18 (95% CI 0.92-1.52; p=0.20). Response rates to the 2 drugs were similar: TMZ 13.5% versus DTIC 12.1%. Quality of life. At 12 weeks, HQoL scores favoured TMZ for physical and global functioning (both at p<0.05). Safety. No major difference was observed, and both treatments were well-tolerated. malignant melanoma, surgery. Until death. Duration of survival. incurable by Progression-free survival, objective response in patients with measurable disease, duration of response, safety and tolerability. Estimated cost and cost impact The cost of treatment with temozolomide for this indication is not yet publicly known. DTIC per 42 days (2 x 21 day cycles) costs £110.92, with additional intravenous administration costs. 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 Other: Services Increased use e.g. length of stay, Service reorganisation required out-patient visits ; Decreased use: reduced out-patient treatment. Staff or training required ; Increased unit cost compared to Increased costs: capital investment needed Other: Costs alternative New costs: April 2007 Increased costs: more patients coming for treatment ; Savings: oral formulation (intended to replace current inpatient intravenous treatment) 4 National Horizon Scanning Centre News on emerging technologies in healthcare References 1 NICE Guidance on Cancer Services. Improving outcomes for people with skin tumours including melanoma, the manual. National Collaborating Centre for cancer, February 2006. 2 NICE Guidance on Cancer Services. Improving supportive and palliative care for adults with cancer, March 2004. 3 Scottish Intercollegiate Guidelines Network (SIGN): Cutaneous melanoma – a national clinical guideline. No. 72, published July 2003, updated February 2004. 4 Roberts DLL, Anstey AV, Barlow RJ et al. On behalf of the British Association of Dermatologists and the Melanoma Study Group. UK guildelines for the management of cutaneous melanoma. Br J Dermatol 2002; 146: 7-127. 5 Quirt I, Verma S, Petrella K, et al. Temozolomide for the treatment of metastatic melanoma: a clinical practice guideline for the Program in Evidence-Based Care and Cancer Care Ontario, March 2006. 6 Office of National Statistics (ONS): 2004 incidence data and 2005 mortality data for ICD code C43. Available at www.statistics.gov.uk/ 7 Balch CM, Soong S-J, Gershenwald JE et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19 (16): 3622-3634. 8 Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1) 2000; 15:158-166. 9 Lee ML, Tomsu K & Von Eschen KB. Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Research 2000; 10(1): 81-92. 10 Sasse AD, Sasse EC, Clark LG et al. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database of Systematic Reviews 2007, Issue 1, Art No. CD005413. DOI 10.1002/14651858. 11 Huncharek M, Caubet JF & McGarry R. Single-agent DTIC versus combination therapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3,273 patients from 20 randomised trials. Melanoma Research. 2001; 11(1): 75-81. The National Horizon Scanning Centre is a constituent of the NHS National Institute for Health Research and is managed under contract from the Department of Health's R&D Division. The views expressed in NHSC publications are those of the author(s). They are not necessarily shared by the Department of Health and should not be taken as representing Government policy. The National Horizon Scanning Centre, 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 April 2007 5