National Horizon Scanning Centre. Ipilimumab (MDX-010) for unresectable stage III or IV metastatic melanoma - first or second line treatment

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Ipilimumab (MDX-010) for unresectable stage III or IV metastatic melanoma - first or second line treatment April 2008 This technology summary is based on information available at the time of research

1 Ipilimumab (MDX-010) for unresectable stage III or IV metastatic melanoma - first or second line treatment April 2008 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 Ipilimumab (MDX-010) for unresectable stage III or IV metastatic melanoma - first or second line treatment Target group Metastatic melanoma unresectable stage III or IV: First line in combination with dacarbazine Second line monotherapy Technology description Ipilimumab (MDX-010) is an intravenous (IV) fully-human anti-cytotoxic T-lymphocyte antigen-4 (anti-ctla-4) monoclonal antibody. CTLA-4 is an inducible receptor expressed by T-lymphocytes which, when activated, inhibits T-lymphocyte proliferation and function. Ipilimumab blocks CTLA-4, preventing binding of B7 molecules which enables continued CD28-mediated enhancement of T-lymphocyte receptor signalling. Ipilimumab is currently in phase II and III clinical trials for metastatic melanoma, and phase II clinical trials for lung cancer, prostate cancer, bladder cancer, breast cancer, and pancreatic cancer. Innovation and/or advantages Ipilimumab is a biologic agent with a novel mechanism of action and available survival data from phase II studies are promising. Developer Bristol-Myers Squibb; Medarex 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 (2000). Relevant guidance NICE Cancer Service Guidance. Improving outcomes for people with skin tumours including melanoma NICE Cancer Service Guidance. Improving supportive and palliative care for adults with cancer SIGN. National clinical guideline on cutaneous melanoma (updated 2004). British Association of Dermatologists and the Melanoma Study Group. UK guidelines for the management of cutaneous melanoma Canadian clinical practice guideline (for the Program in Evidence-Based Care and Cancer Care Ontario): temozolomide for the treatment of metastatic melanoma Cutaneous malignant melanoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up Clinical need and burden of disease The incidence of malignant melanoma is increasing in England and Wales, with rates doubling approximately every years 7. There were 7,363 new cases of malignant melanoma registered in England in 2004, and 1,622 deaths in England and Wales in Although malignant melanoma prognosis and survival has improved over the 2

3 years, advanced disease still has limited treatment options and generally low survival rates. Younger patients tend to have higher survival rates than older patients; women have a higher survival and lower age-specific mortality rate than men, whilst higher survival rates have been noted in the most affluent, compared to the least affluent societal groups 9. Five-year survival for stage III disease is around 40-50%, and for stage IV disease around 20-30% 10 (median survival is between 6-9 months) 11. Existing comparators and treatments Single-agent chemotherapy with dacarbazine (DTIC), an alkylating agent administered intravenously. A 2007 Cochrane review 12 found that cytotoxic alternatives to DTIC, including temozolomide, cisplatin, 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 13. 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 code, CA name, phase Dacarbazine with ipilimumab vs. dacarbazine with placebo; phase III CA Ipilimumab with or without budesonide; phase II. Sponsor BMS; Medarex. BMS; Medarex. Status Ongoing. Completed. Location Europe, USA, Canada, South Europe, USA, Canada. America, Africa. Design Randomised, double-blind, placebo Randomised; double blind. control. Participants in trial n=500 (expected); adults; treatment naïve stage III or IV melanoma. Arm A: Ipilimumab 10mg/kg every 3 wks for 10 wks, then 10mg/kg every 12 wks starting at wk 24; and dacarbazine 850mg/m 2 every 3 wks for 22 wks; or Arm B: Placebo given at the same schedule as ipilimumab in arm A and dacarbazine the same as in arm A. n=110 (expected); adults; unresectable stage III or IV malignant melanoma. Arm A: Ipilimumab with budesonide; or Arm B: Ipilimumab without budesonide. Follow-up Until death or termination of study. Tumour re-staging at week 24; then until death. Primary outcome Progression free survival (PFS). Adverse events (diarrhoea grade 2,3,4). Secondary outcomes Efficacy; safety; quality of life (QoL). Key results - - Expected - - reporting date Adverse effects - - Safety; objective response rate; disease control rate; PFS; overall survival (OS). 3

4 Trial code, name, phase CA Ipilimumab monotherapy; phase II CA Ipilimumab monotherapy; phase II Sponsor BMS; Medarex. BMS; Medarex. BMS. Status Completed. Completed. Ongoing. Location Europe, Australia, USA, Canada, South America, Africa. Europe, US. Design Participants in trial Follow-up Randomised; double blind; uncontrolled. n=210; adults; previously treated, therapy-refractory or intolerant unresectable stage III or IV melanoma. Ipilimumab 0.3, 3, or 10 mg/kg. Until death or entry into companion study. Non-randomised; open label; uncontrolled. n=150; adults; previously treated unresectable stage III or stage IV melanoma. Single treatment arm: Ipilimumab. Until death, termination of study, or entry into companion study. Primary Objective response rate. Objective response rate. Safety. outcome Secondary outcomes Safety; PFS; OS; QoL. Disease control rate; PFS; OS; safety; QoL. Adverse effects Estimated cost and cost impact The cost of ipilimumab has not yet been determined. CA Extension study; phase II Europe, USA, Canada, South America, Africa. Non-randomised, open label, uncontrolled. n=200 (expected); adults; advanced melanoma; prior treatment in an ipilimumab study. Ipilimumab 3 or 10mg/kg every 3 weeks or every 3 months. Until death or termination of study. OS; immune breakthrough events. Dacarbazine 850mg/m 2 IV once every 3 weeks for 22 weeks for an average 1.7m 2 person costs around 338 (assuming wastage). This does not include service costs associated with IV administration. 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 None identified Services Increased use: an additional IV treatment option Service reorganisation required Staff or training required Decreased use Other: None identified 4

5 References 1 NICE Guidance on Cancer Services. Improving outcomes for people with skin tumours including melanoma, the manual. National Collaborating Centre for cancer. February NICE Guidance on Cancer Services. Improving supportive and palliative care for adults with cancer. March Scottish Intercollegiate Guidelines Network (SIGN): Cutaneous melanoma a national clinical guideline. No. 72, published July 2003, updated February Roberts DLL, Anstey AV, Barlow RJ et al. On behalf of the British Association of Dermatologists and the Melanoma Study Group. UK guidelines for the management of cutaneous melanoma. Br J Dermatol 2002; 146: 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 Cutaneous malignant melanoma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Annals of Oncology 18 (Supplement 2): ii71-ii73, Lens MB, Dawes M. Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 2004; 150: Office of National Statistics (ONS): 2004 incidence data and 2005 mortality data for ICD code C43. Available at: (Accessed 10/03/2008). 9 Cancer Research UK. Malignant melanoma. CancerStats - January Available at: (Accessed 10/03/2008). 10 Cancer Research UK. Melanoma statistics and outlook. Available at: (Accessed 10/03/2008). 11 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): 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. CD DOI / 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): Clinical Trials. Dacarbazine and ipilimumab vs. dacarbazine with placebo in untreated unresectable stage III or IV melanoma. Available at: (Accessed 20/03/2008). 15 Clinical Trials. A study of MDX-010 (BMS ) administered with or without prophylactic oral budesonide. Available at: (Accessed 20/03/2008). 16 Clinical Trials. Study of ipilimumab (MDX-010) monotherapy in patients with previously treated unresectable stage III or IV melanoma. Available at: (Accessed 20/03/2008). 17 Clinical Trials. A single arm study of ipilimumab monotherapy in patients with previously treated unresectable stage III or IV melanoma. Available at: (Accessed 20/03/2008). 18 Clinical Trials. A companion study for patients enrolled in prior/parent ipilimumab studies. Available at: (Accessed 20/03/2008). 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) Fax +44 (0)

Horizon Scanning Technology Summary. Temozolomide (Temodal) for advanced metastatic melanoma. National Horizon Scanning Centre.

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