Temsirolimus (Torisel) for mantle cell lymphoma - relapsed and/or refractory January 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
Temsirolimus (Torisel) for mantle cell lymphoma - relapsed and/or refractory Target group Mantle cell lymphoma (MCL) - relapsed and/or refractory. Background Mantle cell lymphoma is a cancer of the B-cell lymphocytes, and an aggressive form of non-hodgkin s lymphoma (NHL). Technology description Temsirolimus (Torisel, CCI-779) is a mammalian target of rapamycin (mtor) signal transduction inhibitor, which blocks a number of signal transduction pathways involved in cell cycle regulation. It is administered by intravenous infusion (iv), with an anticipated dose regime for MCL of 175mg once weekly for three weeks, followed by 75mg once weekly until progression or unacceptable toxicity occurs. Temsirolimus is licensed for the first-line treatment of advanced renal cell carcinoma, and is also in development for other indications, including non-small cell lung cancer, hepatocellular cancer and ovarian cancer. Innovation and/or advantages Temsirolimus is the first in a new drug class of mtor inhibitors, and may provide a new and relatively well-tolerated therapy option for patients with relapsed and/or refractory MCL. Developer Wyeth Pharmaceuticals. 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: In phase III clinical trials. Temsirolimus has been designated an orphan drug for MCL in Europe. NHS or Government priority area: This topic is relevant to the NHS Cancer Plan. Relevant guidance NICE technology appraisal in development. Renal cell carcinoma: bevacizumab, sorafenib, sunitinib and temsirolimus. Expected January 2009 1. NICE technology appraisal. Non-Hodgkin s lymphoma: rituximab. 2003 2. British Committee for Standards in Haematology: Haemato-Oncology Task Force. Guidelines on diagnosis and therapy: nodal non-hodgkin's lymphoma. 2002. 3 2
Clinical need and burden of disease MCL is a rare condition, accounting for around 5-6% of all NHL cases 4. In England and Wales there were 8,841 new cases of NHL registered in 2004, equating to an estimated 442 to 530 new cases of MCL 5. It can occur at any age from the late 30s to old age but is more common in the over 50s, and is three times more common in men than in women 6. Despite favourable initial therapeutic response rates, most MCL patients relapse (median overall survival: 3-5 years 7 ). Following initial relapse, median overall survival falls to 1-2 years. 8 Existing comparators and treatments Chemotherapy is the mainstay of first and second-line management, and may be used in combination with radiotherapy, interferon and steroidal therapies. High-dose chemotherapy with stem cell or bone marrow transplantation may be used in younger patients. First-line chemotherapy-based options include: CHOP: vincristine, doxorubicin, cyclophosphamide and prednisolone. CHOP-R: as above plus ritiximab (widely seen as standard). CVP: cyclophosphamide, vincristine and prednisone. FCR: fludarabine with cyclophosphamide and rituximab. Patients with multi-relapsed disease often become intolerant to combination chemotherapies 9. There is currently no standard of care for this group, and a range of single agent therapies are used, including fludarabine, chlorambucil, gemcitabine, etoposide, cladribine, thalidomide, vinblastine, Mab Campath 1H, and lenalidomide. Efficacy and safety Trial name N0186. Relapsed, refractory; phase II 3066K1-305-WW/ NCT00117598. Relapsed, refractory; active control; phase III NCT00109967. Relapsed, refractory; temsirolimus with rituximab; phase II Sponsor NCI CTEP a Wyeth NCI CTEP Status Published 10 In progress In progress (started May 2005) Location USA USA, Canada USA Design Cohort study Open-label, randomised, active control Participants in trial n=35 (34 eligible for efficacy); adults; relapsed or refractory MCL. Temsirolimus 250mg iv every week for 12 cycles (if tumour response after 6 cycles) or 2 cycles after complete remission. (cycle = 4 weeks). n=177; adults; relapsed or refractory MCL. Temsirolimus at 2 dose levels vs investigators choice of therapy. Open-label n=73; adults; relapsed or refractory MCL. Temsirolimus 25mg iv once a week for 4 weeks + rituximab iv once a week for 4 weeks during cycle 1 (cycle = 4 weeks), and once in week 1 during cycle 3, 5, 7, 9 and 11 (dose levels not disclosed). Repeated every 4 weeks for up to 12 cycles. a National Cancer Institute Cancer Therapy Evaluation Program. 3
Follow-up Interim analysis after n=18 accrued and follow-up for 24 weeks. Primary outcome Secondary outcomes Overall response rate (ORR); median time to progression (TTP); median duration of response. Key results ORR 38% (90% CI: 24-54%). Median TTP 6.5 months (95% CI: 2.9-8.3 months). Median duration of response was 6.9 months (95% CI: 5.2-12.4 months). Adverse effects Haematological toxicities: grade 3: 71%, grade 4: 11%. Thrombocytopenia was the most common cause of dose reductions. Progression free survival. Safety and tolerability, objective response rate, overall survival. Not yet available. - - Up to five years. Response rates. Time to disease progression, time to event analysis of response, toxicity. Not yet available. Estimated cost and cost impact The price for temsirolimus has yet to be agreed with the Department of Health. The anticipated unit price ( 515 per 25mg vial) is based on the dosing requirements for the treatment of advanced renal cell carcinoma. Treatment of MCL will require higher doses of temsirolimus. The costs of iv administration and antihistamine infusion prior to each treatment will be additional. Patients Reduced morbidity Quicker, earlier or more accurate diagnosis or identification of disease Reduced mortality or increased survival Other: Improved quality of life for patients and/or carers None identified Services Increased use Service reorganisation required Staff or training required Decreased use Other: None identified Costs Increased unit cost compared to alternative Increased costs: more patients coming for treatment New costs: Savings: Other: Increased costs: capital investment needed References 1 National Institute for Health and Clinical Excellence multiple technology appraisal in development. Renal cell carcinoma: bevacizumab, sorafenib, sunitinib and temsirolimus. Expected January 2009. 2 National Institute for Health and Clinical Excellence technology appraisal. Non-Hodgkin s lymphoma: rituximab. TA65. September 2003. 3 British Committee for Standards in Haematology (BCSH). The Haemato-Oncology Task Force. Guidelines on diagnosis and therapy: nodal non-hodgkin's lymphoma. 2002. 4
4 Williams ME & Densmore JJ. Biology and therapy of mantle cell lymphoma. Curr Opin Oncol 2005;17:425-431. 5 Cancer Research UK, cancer stats. http://www.info.cancerresearchuk.org/cancerstats/ [accessed 15/1/2008]. 6 Cancer Backup. http://www.cancerbackup.org.uk/cancertype/lymphomanon-hodgkin/typesofnhl/ Mantlecell [accessed 15/1/2008]. 7 O Connor OA. Mantle cell lymphoma: identifying novel molecular targets in growth and survival pathways. Hematology 2007;2007:270-276. 8 Khouri IF, Lee MS, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/ recurrent mantle-cell lymphoma. J Clin Oncol 2003;21:4407-4412. 9 Orion MH, Gribben JG, Neuberg DS et al. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol 2002;20(5):1288-1294. 10 Witzig TE, Geyer SM, Ghobrial I et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005;23:5347-5356. The Research Programme is funded by The National Institute for Health Research. 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