Denosumab (AMG 162) for bone metastases from solid tumours and multiple myeloma September 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
Denosumab (AMG 162) for bone metastases from solid tumours and multiple myeloma Target group For treatment of bone metastases to prevent skeletal-related events in patients with: Solid tumours including: o breast cancer o prostate cancer (progressed after treatment with at least one hormonal therapy) Multiple myeloma (MM) Background Solid tumours frequently metastasise to bone. While visceral metastases are more likely to be fatal, patients with only metastases of the bone can survive up to 10 years or more. Factors secreted by tumour cells in bone activate osteoclasts that are responsible for bone resorption. In turn, bone resorption by osteoclasts releases growth factors from the bone matrix that may stimulate tumour growth. This interaction results in bone destruction and increased tumour burden. Skeletal complications of malignancy include fracture, bone pain, hypocalcaemia and spinal cord compression. Technology description Denosumab (AMG 162) is a fully human monoclonal antibody that specifically targets the receptor activator of nuclear factor kappa B ligand (RANKL) and neutralises its activity, thereby inhibiting osteoclast differentiation, activation, and survival which suppresses bone resorption. Denosumab is administered monthly at a dose of 120mg by subcutaneous (SC) injection and is intended to be used in conjunction with standard antineoplastic therapies as a substitute for bisphosphonates (BP). Denosumab suppresses bone resorption regardless of previous BP exposure. Denosumab is also in phase III development for the prevention of cancer treatmentinduced bone loss, and in phase II trials in rheumatoid arthritis. Innovation and/or advantages Denosumab is first in class for this indication. Its SC route of administration distinguishes it from some existing products which are administered intravenously (IV). Denosumab may also have a better adverse effect profile compared to bisphosphonates. Developer Amgen Inc. Availability, launch or marketing dates, and licensing plans: In phase III clinical trials. NHS or Government priority area: This topic is relevant to the Cancer Reform Strategy (2007) and the NHS Cancer Plan (2000). Relevant guidance Metastatic disease NICE clinical guideline. Diagnosis and management of metastatic malignant disease of unknown primary origin. Expected May 2010. SIGN clinical guideline. Control of pain in patients with cancer, 2000 1. 2
Breast cancer NICE technology appraisals for advanced breast cancer: gemcitabine (2007 2 ), trastuzumab (2002 3 ), vinorelbine (2002 4 ), taxanes (docetaxel and paclitaxel, 2001 5 ). NICE has recommended capecitabine (2003 6 ) as an option for treatment in line with the licensed indication for locally advanced or metastatic breast cancer. NICE technology appraisal. Lapatinib for the treatment of advanced or metastatic breast cancer. Publication date to be announced. NICE clinical guideline. Advanced breast cancer diagnosis and treatment. Expected January 2009. NICE cancer service guidance. Improving outcomes in breast cancer. 2002 7. SIGN clinical guideline. Management of breast cancer in women. 2005 8. Prostate cancer NICE technology appraisal. Docetaxel for the treatment of hormone refractory metastatic prostate cancer. 2006 9. NICE clinical guideline. Prostate cancer: diagnosis and treatment. 2008 10. NICE cancer service guidance. Improving outcomes in urological cancers - Manual. 2002 11. Multiple myeloma NICE technology appraisal. Bortezomib monotherapy for relapsed multiple myeloma. October 2007 12. NICE technology appraisal. Lenolidamide for multiple myeloma in people who have received at least one prior therapy. Expected January 2009. NICE cancer service guideline. Haemato-oncology. 2003 13. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of multiple myeloma 2005. 2006 14. British Committee for Standards in Haematology. Guidelines on the use of colonystimulating factors in haematological malignancies. 2003 15. Clinical need and burden of disease Bone metastases from breast and prostate cancers account for more than 80% of all cases of metastatic bone disease 16. The incidence of bone involvement in advanced breast and prostate cancer is around 65-75%, and in advanced multiple myeloma is 95-100% 17. Survival rates for patients with bone metastases vary depending on the primary tumour type. The clinical course of bone metastases in multiple myeloma can be relatively short, with a median survival of 20 months after diagnosis of bone metastases, and a 10% probability of surviving 5 years. In breast cancer, median survival is 24 months with a 5 year survival rate of 20%. The best prognosis is in prostate cancer, with a 5-year survival rate of 25% and a median survival of 40 months 17. Between 16-20% of women presenting with breast cancer have advanced disease with distant metastases 3, while up to 22% of newly diagnosed prostate cancers are advanced by time they are detected 18. On the basis that 65-75% of patients with advanced breast and prostate will have bone metastases, and all new cases of multiple myeloma, the potential patient group population for denosumab is estimated to be between 12,000 14,500 patients in England and Wales 19,20,21. Existing comparators and treatments Bisphosphonates clodronate (oral), pamidronate (IV), ibandronate (oral and IV) and zoledronic acid (IV) are used in the management of bone damage and relief of 3
pain from bone lesions in advanced malignancies. Apart from zoledronic acid, licenses are restricted to use in certain cancers. Palliative radiation therapy to reduce localised bone pain. Chemotherapy. Orthopaedic surgery to repair fractures. Efficacy and safety Trial code Prostate, breast or MM denosumab vs IV BP; phase II 22 Breast cancer - denosumab vs IV BP; phase II 23 MM relapsed or plateau denosumab; phase II 24 MM or breast cancer - denosumab vs IV pamidronate; phase II 25 Sponsor Amgen Inc Amgen Inc. Amgen Inc. Amgen Inc. Status Published abstract Published abstract Published abstract Published Location USA, Europe USA, Europe USA, Europe USA, Europe Design Participants in trial Randomised, active comparator n=111; prior BP use (mainly zoledronic acid). continue IV BP every 4 weeks; or denosumab 180mg SC every 12 weeks, or every 4 weeks. Randomised, active comparator n=254; IV BP naïve; confirmed metastasis. 1 of 5 increasing doses of denosumab (30-180mg every 4 weeks or 60-180mg every 12 weeks) or IV BP. Follow-up 25 weeks. 25 weeks efficacy; 57 weeks safety. Primary Median reduction outcome untx at week 25. Secondary outcomes Key results Adverse events (AE) Bone resorption marker - urinary NTx (untx) <50nM at week 13. Skeletal related events (SREs); safety. untx <50nM at week 13: denosumab 71% vs IV BP 29%. At week 25: 64% denosumab vs 37% IV BP. At 25 weeks denosumab associated with fewer SREs (8%) than IV BP (20%). Bone pain, nausea, anaemia. One serious AE (hypophosphatemia) untx >65% reduction; 1 SRE; safety. untx reduction: denosumab 75% vs 71% IV BP. On study SRE 12% denosumab vs 16% BP. No denosumab antibodies detected at week 57. Grade 3 or 4 AEs similar between groups. 28% denosumab vs 47% Single arm cohort n=85; relapsed or plateau disease. Received denosumab 120mg every 4 weeks (loading dose 120mg on days 1, 8, and 15 of 1 st cycle) for 6 months. Randomised double-blind, active comparator n=54 (breast cancer n=29; MM n=25). Confirmed metastasis. single dose denosumab (0.1-3.0 mg/kg SC); or pamidronate (90mg IV). 1-12 months. Single dose study. Complete (CR) or partial response (PR) - includes 50% reduction serum M protein. 25% reduction in serum M protein; safety. No CR or PR observed. 25% of relapsed cohort had stable disease for >6 months vs 59% in plateau cohort. 6-13% in respective cohorts reached secondary endpoint. Serious AEs in 19 patients included thrombocytopenia Reduction in untx. Change in serum NTx. Denosumab (1mg/kg) 73% reduction in untx (breast cancer), 77% reduction (MM) vs 30% and 24%, respectively for pamidronate. Reduction sustained for at least 84 days with denosumab. Grade 3 or 4 AEs similar between both groups. 4
possibly related to denosumab. IV BP reported an acute phase reaction 26., pneumonia, relapsed MM, and renal failure. Trial code Prostate cancer - denosumab vs zoledronic acid; phase III; NCT 00321620 Breast cancer (advanced) - Denosumab vs zoledronic acid; phase III; NCT 00321464 Advanced cancer (excluding breast and prostate), or MM - denosumab vs zoledronic acid; phase III; NCT00330759 MM relapsed or plateau; phase II; NCT00259740 Sponsor Amgen Inc. Amgen Inc. Amgen Inc. Amgen Inc. Status Ongoing Ongoing Ongoing Ongoing Location Worldwide (inc UK) Worldwide (inc Worldwide (inc USA and Australia UK) UK) Design Randomised, doubleblind, active comparator. Randomised, double-blind, active comparator. Randomised, double-blind, active Open-label, comparative cohort. Participants in trial n=1,700; failure of at least one hormonal therapy; rising PSA; BP naïve; at least 1 bone metastasis. denosumab 120mg with IV placebo, or zoledronic acid 4mg IV with SC placebo; every 4 weeks. n=1,960; BP naïve; at least 1 bone metastasis. denosumab 120mg with IV placebo or zoledronic acid 4mg IV with SC placebo; every 4 weeks. comparator. n= 1,690; BP naïve; at least 1 bone metastasis. denosumab 120mg with IV placebo or zoledronic acid 4mg IV with SC placebo; every 4 weeks. n=96; BP deprived for at least 2 weeks. Denosumab 120mg on day 1 of a monthly cycle (loading dose 120mg on days 1, 8, and 15 of 1 st cycle). Follow-up Primary outcome Secondary outcomes Expected reporting date At least 33 months (event driven; 745 required). Time to first on-study SRE (noninferiority). Time to first on-study SRE (superiority); laboratory values; anti-denosumab antibodies. Q3/4 2009. Health resource utilisation arm included. Event driven; 745 required. SRE (noninferiority). SRE (superiority). Q3/4 2009. Health resource utilisation arm included. Event driven. SRE (noninferiority). SRE (superiority). 2009. Health resource utilisation arm included. 6 months. Complete response (CR) or partial response (PR). CR, PR or minor response (MR); CR-only; safety. August 2009. Estimated cost and cost impact The cost of denosumab is currently unknown. As a subcutaneous therapy, the cost of administration will be reduced compared to IV therapies. 5
Drug Indication Dose Annual cost Pamidronate Bone metastases in breast cancer or MM. 90mg IV (over 1-2h) every 4 weeks. 2,145 Zoledronic acid Advanced malignancies involving bone. 4mg IV (over 15 minutes) 2,535-3,315 every 3-4 weeks. Ibandronic acid Bone metastases in breast cancer. 6mg IV every 3-4 weeks or 50mg daily (oral). 2,535 Potential or intended impact speculative 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: SC rather than IV administration Other: patient training will be required if self-administration is planned None identified Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: Savings: Other: unknown References 1 Control of pain in patients with cancer. Scottish Intercollegiate Guideline Network. Guideline 44, June 2000. 2 National Institute for Health and Clinical Excellence. Gemcitabine for the treatment of metastatic breast cancer. Technology Appraisal TA116. January 2007. 3 National Institute for Health and Clinical Excellence. Guidance on the use of trastuzumab for advanced breast cancer: The clinical effectiveness and cost effectiveness of trastuzumab for breast cancer. Technology Appraisal TA34. March 2002. 4 National Institute for Health and Clinical Excellence. Guidance on the use of vinorelbine for advanced breast cancer: The clinical effectiveness and cost effectiveness of vinorelbine for breast cancer. Technology Appraisal TA54. December 2002. 5 National Institute for Health and Clinical Excellence. Guidance on the use of taxanes for advanced breast cancer: Taxanes for the treatment of breast cancer. Technology Appraisal TA30. September 2001. 6 National Institute for Health and Clinical Excellence. Guidance on the use of capecitabine for the treatment of locally advanced or metastatic breast cancer. Technology Appraisal TA62. May 2003. 7 National Institute for Health and Clinical Excellence. Improving outcomes in breast cancer. Cancer service guidance. August 2002. 8 Scottish Intercollegiate Guideline Network. Management of breast cancer in women. Guideline 84, December 2005. 9 National Institute for Health and Clinical Excellence. Docetaxel for the treatment of hormone refractory metastatic prostate cancer. Technology Appraisal TA101. June 2006. 10 National Institute for Health and Clinical Excellence. Prostate cancer: diagnosis and treatment. Clinical guideline CG58. February 2008. 11 National Institute for Health and Clinical Excellence. Improving outcomes in urological cancers - Manual. Cancer service guidance. September 2002. 12 National Institute for Health and Clinical Excellence. Bortezomib monotherapy for relapsed multiple myeloma. Technology Appraisal 129. October 2007. 6
13 National Institute for Health and Clinical Excellence. Cancer Service Guideline. Improving outcomes in haemato-oncology cancer. October 2003. 14 Smith A, Wisloff F, Samson D. Guidelines on the diagnosis and management of multiple myeloma 2005 on behalf of the UK Myeloma Forum, Nordic Myeloma Study Group and British Committee for Standards in Haematology. British Journal of Haematology, 2006;132:410-451. 15 British Committee for Standards in Haematology. Guidelines on the use of colony-stimulating factors in haematological malignancies. British Journal of Haematology, 2003;125: 22-33. 16 Coleman RE. Bisphosphonates: Clinical experience. The Oncologist. 2004; 9 (suppl 4): 16-27. 17 Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80 (suppl 8): 1588-1594. 18 Evans HS, Moller H. Recent trends in prostate cancer incidence and mortality in southeast England. European Urology. 2003; 43: 337-341. 19 Cancer Research UK. UK breast cancer incidence statistics. Available online at: http://info.cancerresearchuk.org/cancerstats/types/breast/incidence/. Accessed 04/08/2008. 20 Cancer Research UK. UK multiple myeloma incidence statistics. Available online at http://info.cancerresearchuk.org/cancerstats/types/multiplemyeloma/incidence/. Accessed 04/08/2008. 21 Cancer Research UK. UK prostate cancer incidence statistics. Available online at: http://info.cancerresearchuk.org/cancerstats/types/prostate/incidence/. Accessed 04/08/2008. 22 Fizazi K, Lipton A, Mariette X et al. Denosumab in patients with bone metastases from prostate, breast and other cancers and elevated urinary N-telopeptide (untx) during intravenous bisphosphonate (IV BP) therapy: Final results of a phase II study. ASCO Annual Meeting 2008 (abstract 3596). 23 Lipton A, de Boer RH, Figueroa A et al. Phase II study of denosumab in breast cancer patients with bone metastases naïve to intravenous bisphosphonate therapy: Extended efficacy and safety analysis. ASCO Breast Cancer Symposium 2007 (abstract 266). 24 Vij R, Horvath N, Spencer A. An open-label phase 2 trial of denosumab in the treatment of relapsed or plateau phase multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2007 (abstract 3604). 25 Body J-J, Facon T, Coleman RE et al. A study of the biological receptor activator of nuclear factor-kappa ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clinical Cancer Research. 2006; 12 (4):1221-1228. 26 Campbell-Baird C. Lipton A, Sarkeshik M et al. Incidence of acute-phase events following denosumab therapy: Results from a randomised, controlled phase II study in patients with breast cancer and bone metastases. ASCO Breast Cancer Symposium 2007 (abstract 198). 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, 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 7