Sunitinib (Sutent) for advanced and/or metastatic breast cancer December 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. The Research Programme is part of the National Institute for Health Research
Sunitinib (Sutent) for advanced and/or metastatic breast cancer Target group: Breast cancer - advanced and/or metastatic: o First line in combination with paclitaxel/docetaxel o Second line monotherapy o Second line in combination with capecitabine after failure of taxanes and anthracyclines due to resistance or intolerance. Technology description Sunitinib malate (Sutent, SU11248) is an oral multi-targeted tyrosine kinase inhibitor with anti-tumour and anti-angiogenic activity in development for first and second line treatment of advanced and/or metastatic breast cancer. Sunitinib inhibits the plateletderived growth factor (PDGF), vascular endothelial growth factor (VEGF), KIT and FLT3 receptors on cancer cells, vascular endothelial cells and pericytes. Sunitinib is administered orally in a six week cycle; 50mg per day for four weeks, followed by a break of two weeks before repeating the cycle until disease progression. Trials are also investigating a continuous dose of 37.5mg. Sunitinib (Sutent) is currently licensed for the treatment of: advanced and/or metastatic renal cell carcinoma. unresectable and/or metastatic malignant gastro-intestinal stromal tumours (GIST) after failure of imatinib mesylate due to resistance or intolerance. Sunitinib is currently in phase II trials for neoadjuvant treatment of newly diagnosed resectable stage II-IIIA breast cancer as a monotherapy and in combination with chemotherapy in stage II-IIIB breast cancer. Sunitinib is also in phase III trials for nonsmall cell lung cancer, and metastatic colorectal cancer refractory to 5FU, irinotecan and oxaliplatin. Innovation and/or advantages Sunitinib may increase response rates and progression free survival in patients with metastatic breast cancer. It will add another treatment option for patients with advanced disease, and as an oral treatment, it may be possible to manage patients on an outpatient basis if used as a monotherapy. Developer Pfizer Ltd. Place of use Home care e.g. home dialysis Secondary care e.g. general, non-specialist 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: Suntinib is in phase III clinical trials for first and second line advanced and/or metastatic breast cancer. 2
NHS or Government priority area: This topic is relevant to the NHS Cancer Plan Relevant guidance NICE clinical guidelines in progress (due January 2009): o Advanced breast cancer diagnosis and treatment o Early breast cancer diagnosis and treatment SIGN clinical guideline. Management of breast cancer in women, 2005 1. NICE cancer service guidance - Improving outcomes in breast cancer, 2002 2. NICE Technology Appraisals Advanced breast cancer: trastuzumab (2002 3 ), taxanes (docetaxel and paclitaxel, 2001 4 ), vinorelbine (2002 5 ), gemcitabine (2007 6 ) and capecitabine (2003 7 ). Early stage breast cancer: adjuvant hormonal therapies (2006 8 ), and for adjuvant treatment - trastuzumab (2006 9 ), docetaxel (2006 10 ) and paclitaxel (2006 11 ). Clinical need and burden of disease Breast cancer is the most common malignancy affecting women in the UK. There were 39,301 women newly diagnosed with breast cancer in England and Wales during 2004 12 and in 2005 there were 10,969 deaths, a rate of 40 deaths per 100,000 females 13. Advanced and metastatic breast cancer are defined by clinical staging based on the tumour, node and metastasis staging system, falling within stage III and stage IV. Between 16% and 20% of women (an estimated 6,288 to 7,860 women) presenting with breast cancer have advanced disease with distant metastases 3, and in 2002 NICE estimated that around 50% of those presenting with early or localised breast cancer will eventually develop metastatic breast cancer 3. Existing comparators and treatments The role of current treatments for advanced and metastatic breast cancer is to palliate symptoms, prolong survival and maintain a good quality of life. The choice of treatment is based on previous therapy, oestrogen receptor status, HER2 status and the extent of the disease. Current options include: First line systemic therapy for oestrogen receptor-negative disease is chemotherapy (usually an anthracycline based regimen a or a combination of cyclophosphamide, methotrexate and fluorouracil). Hormone manipulation therapy for oestrogen receptor positive tumours. Following disease progression on an anthracycline, other chemotherapy options include single-agent taxanes, capecitabine (in combination with docetaxel or as monotherapy), bevacizumab (in combination with paclitaxel), vinorelbine and gemcitabine in combination with paclitaxel. Trastuzumab in combination with taxanes is given to those with HER2+ metastatic disease. It may also be given on its own in women with advanced breast cancer who have already received at least two courses of chemotherapy 14. a Anthracycline based regimens include AC (doxorubicin and cyclophosphamide), EC (epirubicin and cyclophosphamide), CAF (cyclophosphamide, doxorubicin and fluorouracil), FEC (fluorouracil, epirubicin and cyclophosphamide) 3
Efficacy and safety One phase I conference abstract 15 has reported on the use of sunitinib in combination with paclitaxel for first-line treatment of metastatic breast cancer. There are several ongoing phase II trials of sunitinib as either a monotherapy, or in combination for first and second line treatment of metastatic breast cancer: First line in combination with bevacizumab and paclitaxel (SABRE-B trial) Second line in combination with trastuzumab Second line monotherapy in triple receptor negative disease Consolidation therapy after response to taxanes Trial name or code Second line monotherapy - phase II 16 SUN 1094: First line in combination: sunitinib + paclitaxel vs. bevacizumab + paclitaxel phase III 17 SUN 1064: First line in combination: sunitninib + docetaxel vs. docetaxel phase III 18 Sponsor Pfizer Pfizer Pfizer Status Conference abstract Ongoing Ongoing Location USA USA USA, Europe (incl UK) Design Open-label, single-arm. Randomised, open-label, active-control. Randomised, open-label, active-control. Participants in trial n=64; anthracycline and taxane refractory metastatic breast cancer. Received Sunitinib 50mg daily for 4 weeks in repeating 6 week cycles. n=740 (planned); no prior chemotherapy for advanced disease. Randomised to sunitinib once daily and paclitaxel i.v. once weekly for 3 out of 4 weeks; or bevacizumab i.v. once every 2 weeks and paclitaxel (as above). n=550; no prior chemotherapy for advanced disease. Administered in 3 week cycles, randomised to: Arm A - docetaxel i.v. on day 1, sunitinib on day 2-15, no treatment days 16-21, or Arm B - docetaxel on day 1 every 3 weeks. Follow-up Until disease progression. Until disease progression. Until disease progression. Primary Objective response rate Progression free survival PFS outcome Secondary outcomes Safety Key results Interim analysis on 51 patients: partial response = 7 (14%); stable disease >6 months = 1 (2%). Expected reporting date Adverse effects (PFS) Safety; tumour control; survival; patient reported outcomes. - - - Not known. Study commenced November 2006. Grade 3 adverse events included neutropenia (39%), anaemia (2%), thrombocytopenia (15%), fatigue (5%), diarrhoea (7%), hand-foot syndrome (7%) and hypertension (5%). Dose reductions required in 17%. - - Overall response rate; duration of response; overall survival; patient reported outcomes; safety. Not known. Study commenced February 2007. 4
Trial name or code SUN 1107: Second line monotherapy: Sunitinib vs. capecitabine phase III 19 SUN 1099: Second line in combination: Sunitinib + capecitabine vs. capecitabine phase III 20 Sponsor Pfizer Pfizer Status Ongoing Ongoing Location Europe, Australia USA, Europe (incl UK) Design Randomised, open-label, active-control. Randomised, open-label, active control. Participants in trial n=700 (planned); anthracycline and taxane refractory. Administered as a 37.5mg continuous dose. n=430 (planned); anthracycline and taxane refractory. Administered as a 37.5mg continuous dose. Follow-up Until disease progression. Until disease progression. Primary PFS. PFS. outcome Secondary outcomes Expected reporting Time to tumour progression, overall response rate, duration of response, overall survival, patient reported outcomes, safety. Not known. Study commenced November 2006. Overall response rate; duration of response; overall survival; 2 and 3 yr survival; patient reported outcomes; overall safety profile. Not known. Study commenced February 2007. Estimated cost and cost impact The cost of sunitinib is estimated at approximately 3,140 per six-week cycle, giving an annual cost (based on 8 cycles) of around 25,110 per patient b. At a continuous dose of 37.5mg, the annual cost would be approximately 32,300 per patient. This cost would be in addition to current chemotherapy if used in combination, but as an oral monotherapy, there is the potential for savings through outpatient treatment. 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 Non identified Services Increased use Service reorganisation required Staff or training required Decreased use: oral administration Other: Non identified Costs Increased unit cost compared to alternative: Additional therapy New costs: Increased costs: more patients coming for treatment Savings: oral monotherapy may enable outpatient use. Increased costs: capital investment needed Other: b Costs from BNF 54, September 2007. 5
References 1 Management of breast cancer in women. Scottish Intercollegiate Guideline Network. Guideline 84, December 2005. 2 Improving outcomes in breast cancer. Cancer service guidance. National Institute for Health and Clinical Excellence. August 2002. 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, March 2002; Technology Appraisal Guidance number 34. 4 National Institute for Health and Clinical Excellence. Guidance on the use of taxanes for advanced breast cancer: Taxanes for the treatment of breast cancer, September 2001; Technology Appraisal Guidance number 30. 5 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, December 2002; Technology Appraisal Guidance number 54. 6 National Institute for Health and Clinical Excellence. Gemcitabine for the treatment of metastatic breast cancer, January 2007. Technology Appraisal Guidance number 116. 7 National Institute for Health and Clinical Excellence. Guidance on the use of capecitabine for advanced breast cancer: The clinical effectiveness and cost effectiveness of capecitabine for breast cancer, May 2003; Technology Appraisal Guidance number 62. 8 National Institute for Health and Clinical Excellence. Guidance on the use of hormonal treatments for early stage breast cancer: Hormonal therapies for the adjuvant treatment of early oestrogen-receptor-positive breast cancer, November 2006, Technology Appraisal Guidance number 112. 9 National Institute for Health and Clinical Excellence. Guidance on the use of trastuzumab for early-stage breast cancer: Trastuzumab for the adjuvant treatment of early-stage HER2-positive breast cancer, August 2006; Technology Appraisal Guidance number 107. 10 National Institute for Health and Clinical Excellence. Docetaxel for the adjuvant treatment of early nodepositive breast cancer, September 2006. Technology Appraisal Guidance number 109. 11 National Institute for Health and Clinical Excellence. Paclitaxel for the adjuvant treatment of early nodepositive breast cancer, September 2006. Technology Appraisal Guidance number 108. 12 Cancer Research UK. UK breast cancer incidence statistics. Accessed 15/11/2007. Available online at: Hhttp://info.cancerresearchuk.org/cancerstats/types/breast/incidence/H. 13 Cancer Research UK. UK breast cancer mortality statistics. Accessed 15/11/2007. Available online at: Hhttp://info.cancerresearchuk.org/cancerstats/types/breast/mortality/H. 14 Cancerbackup. Accessed 15/11/2007. Hhttp://www.cancerbackup.org.uk/cancertype/breast/treatment/herceptinH. 15 Kozloff MF, Chuang E, Roy J et al. Preliminary results of a phase I study of sunitinib plus paclitaxel for firstline treatment of advanced breast cancer. ASCO Breast Cancer Symposium 2007 (abstract 163). 16 Miller KD, Burstein HJ, Elias AD et al. Phase II study of SU11248, a multitargeted tyrosine kinase inhibitor (TKI) in patients with previously treated metastatic breast cancer. Breast Cancer Res Treat. 2005; 94 (suppl 1): S61 (abstract 1066). 17 Clinicaltrials.gov. A phase III study of SU011248 plus paclitaxel verus bevacizumab plus paclitaxel in patients with advanced breast cancer. Accessed 9/11/2007. Available online at: Hhttp://clinicaltrials.gov/ct2/show/NCT00373256?term=sunitinib+paclitaxel&rank=2H.. 18 Clinicaltrials.gov. Study of sunitinib in combination with docetaxel in patients with advanced breast cancer. Accessed 9/11/2007. Available online at: Hhttp://clinicaltrials.gov/ct2/show/NCT00393939?term=Sunitinib+docetaxel&rank=1H. 19 Clinicaltrials.gov. A clinical trial comparing efficacy and safety of sunitinib and capecitabine. Accessed 9/11/2007. Available online at: Hhttp://clinicaltrials.gov/ct2/show/NCT00373113?term=sunitinib+capecitabine&rank=1H. 20 Clinicaltrials.gov. A study of sunitinib in combination with capecitabine compared with capecitabine in patients with breast cancer. Accessed 9/11/200. Available online at: Hhttp://clinicaltrials.gov/ct2/show/NCT00435409?term=sunitinib+capecitabine&rank=2H. 6
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