Horizon Scanning Centre November 2012

Vinflunine (Javlor) monotherapy for advanced breast cancer

SUMMARY NIHR HSC ID: 7887

Vinflunine (Javlor) is intended to be used as monotherapy for the treatment of advanced (stage III or IV) breast cancer. If licensed, it would provide an alternative treatment option for this patient group. Vinflunine is a vinca- alkaloid derivative which acts as a inhibitor and is currently licensed for the treatment of adults with metastatic . This briefing is Breast cancer is the most common cancer in the UK, accounting for 31% of based on all cancers in women and affecting around 126 per 100,000 women per year. information In the UK, 48,788 new cases (male and female) were diagnosed in 2009 and available at the 11,633 deaths occurred in 2010. Breast cancer risk is strongly related to age, time of research with 81% of cases occurring in women aged over 50 years. An estimated 5% and a limited of women have metastases at diagnosis and a further 35% will go on to literature search. develop them over the following 10 years. Five year survival rates for women It is not intended with stage III breast cancer is around 50%, however this decreases to approximately 13% with stage IV disease. to be a definitive

statement on the The aim of treatment for advanced breast cancer is to ameliorate symptoms, safety, efficacy or maintain quality of life and prolong survival. Treatment options include effectiveness of several agents, given either as monotherapy or in the health combination. Vinflunine is in a phase III clinical trial comparing its effect on technology overall survival against treatment with alkylating agents. This trial is expected covered and to complete in 2013.

should not be used for commercial purposes or iii

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

 Breast cancer: advanced; stage III or IV – first, second or third line.

TECHNOLOGY

DESCRIPTION

Vinflunine (Javlor) is a vinca-alkaloid derivative which appears to act as a microtubule inhibitor (MTI). Vinflunine destabilises and decreases their growth rate1. Microtubules play a key role in mitosis and inhibitors suppress the microtubule dynamics required for proper mitotic function, effectively blocking progression and resulting in apoptosis1. MTIs, such as , vinca-alkaloids and epithilones have significant clinical activity in multiple tumour types, but their effectiveness is reduced by drug resistance mechanisms. However, vinflunine’s increased in vivo activity suggests a novel mechanism of action. Characterisation of cell death induced by vinflunine has implicated the involvement of the B-cell lymphoma 2 (Bcl-2) protein. Vinflunine is intended to be used as monotherapy for the treatment of advanced (stage III or IV) breast cancer and is administered by intravenous (IV) infusion at 280mg/m2 on day 1 of a 21 day cycle.

Vinflunine is licensed in the UK as monotherapy for the treatment of adult patients with metastatic bladder cancer. The most frequent treatment-related adverse events (AEs) associated with vinflunine when used for its licensed indication include: neutropenia and anaemia; gastrointestinal disorders, especially constipation, anorexia, nausea, stomatitis, mucositis, vomiting, abdominal pain and diarrhoea; and general disorders such as asthenia and fatigue2.

Vinflunine is in phase III trials for non-small cell lung cancer and head and neck cancer, and in phase II trials for renal cancer, colorectal cancer, melanoma and mesothelioma.

INNOVATION and/or ADVANTAGES

If licensed, vinflunine would provide an alternative treatment option for this patient group.

DEVELOPER

Pierre Fabre Medicament.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Breast cancer arises from the tissues of the breast and most commonly originates in the cells that line the ducts3. Breast cancer is categorised as locally advanced when the tumour has spread to locally adjacent tissues and/or lymph nodes. Metastatic breast cancer is the

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presence of disease at distant sites. The most common sites for metastases are the lymph nodes, bone, liver, lungs and brain4.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: Improving Outcomes: A Strategy for Cancer (2011).

CLINICAL NEED and BURDEN OF DISEASE

Breast cancer is the most common cancer in the UK, accounting for 31% of all cancers in women and affecting around 126 per 100,000 women per year5,6. In the UK, 48,788 new cases (male and female) were diagnosed in 20095 and 11,633 deaths occurred in 2010, accounting for around 15% of all female deaths from cancer7. In 2011-12, there were 179,091 hospital admissions for breast cancer (ICD 10: C50) in England, resulting in 120,502 bed days and 182,270 finished consultant episodes 8. Breast cancer risk is strongly related to age, with 81% of cases occurring in women aged over 50 years, and is greater in those from higher socioeconomic groups5. Analysis of breast cancer survival by level of deprivation has consistently shown higher survival for more affluent women5.

An estimated 5% of women have metastases at diagnosis and a further 35% will develop them over the following 10 years9. Estimates of the number of people living with advanced breast cancer vary, but it is estimated that between 16-20% of women presenting with breast cancer have locally advanced disease with distant metastases10. Five year survival rates for women with stage III breast cancer is around 50%, however this decreases to approximately 13% with stage IV disease11.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

 NICE technology appraisal in development. Everolimus in combination with an aromatase inhibitor for the treatment of HER2 negative, oestrogen receptor positive locally advanced or metastatic breast cancer after prior endocrine therapy (ID538). Expected July 201312.  NICE technology appraisal. Bevacizumab in combination with for the first- line treatment of metastatic breast cancer (TA263). August 201213.  NICE technology appraisal. Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor positive breast cancer which over-expresses HER2 (TA257). June 201214.  NICE technology appraisal. for the treatment of locally advanced or metastatic breast cancer (TA250). April 201215.  NICE technology appraisal. Fulvestrant for the treatment of locally advanced or metastatic breast cancer (TA239). December 201116.  NICE technology appraisal. Bevacizumab in combination with a for the first line treatment of metastatic breast cancer (TA214). February 201117.  NICE technology appraisal. for the treatment of metastatic breast cancer (TA116). January 200718.  NICE technology appraisal. Guidance on the use of trastuzumab for the treatment of advanced breast cancer (TA34). March 200219.

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 NICE clinical guideline. Advanced breast cancer – diagnosis and treatment (CG81). February 20099.  NICE clinical guideline. Breast cancer (early & locally advanced): diagnosis and treatment (CG80). February 200920.  NICE clinical guideline. Familial breast cancer: the classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care (CG41). October 200621.  NICE quality standard. Breast cancer (QS12). September 201122.  NICE cancer service guidance. Improving outcomes in breast cancer (CSGBC). August 200223.

Other Guidance

 European Society for Medical Oncology. Locally recurrent or metastatic breast cancer. Clinical practice guidelines for diagnosis, treatment and follow-up. 201224.  SIGN. Management of breast cancer in women. 200525.  Cancer Services Collaborative Improvement Partnership. Breast cancer service improvement guide. 200326.

EXISTING COMPARATORS and TREATMENTS

For women with locally advanced or metastatic disease, the aim of treatment is to ameliorate symptoms, maintain quality of life and prolong survival. The choice of treatment for each patient depends upon many factors, including previous treatment, site of metastases, receptor status of tumour cells, menopausal status, health and informed patient choice. Current management options include9,20,27:  Surgery, if appropriate.  Radiotherapy – for local control and painful bone metastases.  Standard chemotherapy regimens:  For patients who have not received adjuvant chemotherapya: o 5-, and (FEC). o and cyclophosphamide (AC).  For patients not suitable for treatment with (FEC or AC) because they are contraindicated or because they have received prior treatment in the adjuvant or metastatic setting, NICE recommends9: o as first line – expert opinion suggests , nab- paclitaxel or paclitaxel with gemcitabine are also used first-lineb. o or capecitabine as second line – expert opinion suggests capecitabine is the usual second line option in UK practiceb. o Capecitabine or vinorelbine as third line – expert opinion suggests vinorelbine is the usual third line option in UK practiceb (following anthracycline, taxoid and capecitabine therapy28).  Eribulin – expert opinion suggests it is used in preference to vinorelbine after capecitabine by some (not recommended by NICE)b.  Nab-paclitaxel – expert opinion suggests it may be used in women previously treated with docetaxel before vinorelbineb.  Combination therapy may be considered for those with more aggressive disease: o Doxetaxel with capecitabine.

a Expert personal communication.

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o Gemcitabine with paclitaxel – recommended by NICE for metastatic breast cancer only when docetaxel or docetaxel with capecitabine are considered appropriate. o Cyclophosphamide, and 5-fluorouracil (CMF) – rarely usedb.  Hormonal therapy e.g. tamoxifen and aromatase inhibitors (for oestrogen receptor positive breast cancer).  Biological therapies (e.g. trastuzumab for HER2-positive tumours).  Bisphosphonates – for patients with symptomatic bone metastases.

EFFICACY and SAFETY

Trial NCT01091168, EUCTR2009-011118-47-FR; vinflunine vs alkylating agent; phase III. Sponsor Pierre Fabre Medicament. Status Ongoing. Source of Trial registry29. information Location EU (incl UK) and other countries. Design Randomised, active-controlled. Participants n=594 (planned); aged 18-75 years; females; breast cancer; metastatic; ≥2 prior chemotherapy regimens including anthracyclines, taxanes, and vinca- alkaloids, and are no longer candidates for these drugs. Schedule Randomised to vinflunine 280mg/m2 IV on day 1 of a 21 day cycle; or an alkylating agent of physician choice, including cyclophosphamide, , , , or . Follow-up Active treatment continues until disease progression or unacceptable toxicity; then follow-up every month for 6 months, then every 3 months until death. Primary Overall survival. outcome Secondary Tumour response rate; progression free survival; quality of life; adverse events. outcomes Expected Estimated study completion date Q1 2013. reporting date

Trial Vinflunine; phase II. Vinflunine; phase II. Sponsor Investigator led. Investigator led. Status Complete and published. Complete and published. Source of Publication30. Abstract31. information Location EU and South Africa. EU (incl UK), South Africa and Tunisia. Design Non-randomised, single arm. Non-randomised, single arm. Participants n=60; aged ≥18 years; females; breast n=56; females; breast cancer; metastatic; cancer; advanced or metastatic; following failure of anthracycline-based received prior anthracycline/taxane and taxane-based chemotherapy. based therapy. Schedule Vinflunine 320mg/m2 IV every 21 days. Vinflunine 320mg/m2 IV every 21 days. Follow-up Active treatment continues until disease Not reported. progression or unacceptable toxicity. Primary Objective response (complete response Objective response. outcome or partial response). Secondary Duration of response; progression free Duration of response; PFS; OS. outcomes survival (PFS); overall survival (OS).

b Expert personal communication.

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Key results Objective response, 18 out of 60 For treated and evaluable populations patients (response rate 30%); median respectively: response rate, 12.5% and duration of response, 4.8 months (95% 14%; disease control rate, 42.9% and CI 4.2-7.2); median PFS, 3.7 months 51.2%; median PFS, 2.6 months (95%CI (95% CI 2.8-4.2); median OS, 14.3 1.6-4.0); median OS, 11.4 months (95% CI months (95% CI 9.2-19.6). 7.4-14.2); duration of response, 6.8 months (95% CI 5.6-upper limit not reached). Adverse Most common AEs included anaemia Grade 3-4 leucopenia was reported in effects (AEs) (83.3%), leucopenia (91.7%), 49.1%. Grade 3 neutropenia was reported neutropenia (91.7%), constipation in 30.9% of patients and grade 4 in 40% of (63.3%), nausea (58.3%), vomiting patients. Other grade 3 toxicities included (46.7%) and fatigue (81.7%). Grade 3-4 anaemia (5.5%), fatigue (14.3%) and leucopenia was experienced by 40% constipation (7.1%). patients and grade 3-4 neutropenia occurred in 65% of patients.

ESTIMATED COST and IMPACT

COST

Vinflunine is already marketed in the UK for the treatment of metastatic bladder cancer; 250mg (10ml vial) costs £1,062.50 and 50mg (2ml vial) costs £212.50. Treatment with 280mg/m2 for one cycle would cost £2,337.50c,32.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified: there are already a significant number of agents which are used in this setting and UK practiced. c Based on average body surface area of 1.88m2. d Expert personal communication.

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REFERENCES

1 Perez EA. Mictrotubule inhibitors: Differentiating tubulin-inhibiting agenst based on mechanisms of action, clinical activity, and resistance. Molecular Cancer Therapeutics 2009;8(8),2086-2095. 2 The electronic Medicines Compendium (eMC). Summary of Product Characteristics, Javlor. Pierre-Fabre, UK. http://www.medicines.org.uk/EMC/medicine/23127/SPC/Prolia/ Accessed 15 October 2012. 3 Cancer Research UK. Invasive ductal breast cancer. http://cancerhelp.cancerresearchuk.org/type/breast-cancer/about/types/invasive-ductal-breast- cancer Accessed 15 October 2012. 4 Macmillian Cancer Support. Staging and grading of breast cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Symptomsdiagnosis/Staging andgrading.aspx Accessed 15 October 2012. 5 Cancer Research UK. Breast cancer incidence statistics. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/breast/incidence/ Accessed 10 October 2012. 6 Office for National Statistics. Breast cancer. Incidence rates rise, mortality rates fall. 2010. http://www.ons.gov.uk/ons/rel/cancer-unit/breast-cancer-in-england/2010/sum-1.html Accessed 15 October 2012. 7 Cancer Research UK. Breast cancer mortality statistics. http://www.cancerresearchuk.org/cancer- info/cancerstats/types/breast/mortality/ Accessed 10 October 2012. 8 NHS. Hospital episode statistics NHS England 2011-12. HES data 2012. www.hesonline.nhs.uk Accessed 10 October 2012. 9 National Institute for Health and Clinical Excellence. Advanced breast cancer – diagnosis and treatment. Clinical guideline CG81. London: NICE; February 2009. 10 National Institute for Health and Clinical Excellence. Draft scope - gemcitabine for the treatment of locally advanced or metastatic breast cancer. London: NICE; September 2004. 11 Cancer Research UK. Statistics and outlook for breast cancer. http://cancerhelp.cancerresearchuk.org/type/breast-cancer/treatment/statistics-and-outlook-for- breast-cancer#stage Accessed 15 October 2012. 12 National Institute for Health and Clinical Excellence. Everolimus in combination with an aromatase inhibitor for the treatment of HER2 negative, oestrogen receptor positive locally advanced or metastatic breast cancer after prior endocrine therapy. Technology appraisal in development. London: NICE; expected July 2013. 13 National Institute for Health and Clinical Excellence. Bevacizumab in combination with capecitabine for the first-line treatment of metastatic breast cancer. Technology appraisal in development. London: NICE; August 2012. 14 National Institute for Health and Clinical Excellence. Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor positive breast cancer which over-expresses HER2. Technology appraisal in development. London: NICE; June 2012. 15 National Institute for Health and Clinical Excellence. Eribulin for the treatment of locally advanced and metastatic breast cancer. Technology appraisal TA250. London: NICE; April 2012. 16 National Institute for Health and Clinical Excellence. Technology appraisal TA239. Fulvestrant for the treatment of locally advanced or metastatic breast cancer. London: NICE; December 2011. 17 National Institute for Health and Clinical Excellence. Technology appraisal TA214. Bevacizumab in combination with a taxane for the first-line treatment of metastatic breast cancer. London: NICE; February 2011. 18 National Institute for Health and Clinical Excellence. Breast cancer - gemcitabine for the treatment of metastatic breast cancer. Technology appraisal TA116. London: NICE; January 2007. 19 National Institute for Health and Clinical Excellence. Guidance on the use of trastuzumab for the treatment of advanced breast cancer. Technology appraisal TA34. London: NICE; March 2002. 20 National Institute for Health and Clinical Excellence. Breast cancer (early & locally advanced): diagnosis and treatment. Clinical guideline CG80. London: NICE; February 2009. 21 National Institute for Health and Clinical Excellence. Familial breast cancer. Clinical guideline CG41. London: NICE; October 2006.

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22 National institute for Health and clinical excellence. Breast cancer quality service. QS12. London: NICE; September 2011. 23 National Institute for Health and Clinical Excellence. Improving outcomes in breast cancer. Cancer service guidance CSGBC. London: NICE; August 2002. 24 European Society for Medical Oncology. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23(suppl 7):11-19. 25 Scottish Intercollegiate Guidelines Network. Management of breast cancer in women. Clinical guideline No. 84. Edinburgh: SIGN; December 2005. 26 Cancer Services Collaborative Improvement Partnership. Breast cancer service improvement guide. October 2003. 27 Macmillan Cancer Support. Treating breast cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breast/Treatingbreastcancer/Treatin gbreastcancer.aspx Accessed 10 October 2012. 28 NIHR Horizon Scanning Centre. Vinflunine (Javlor) with capecitabine for advanced breast cancer. Birmigham: NIHR HSC; June 2012. 29 ClinicalTrials.gov. Trial of vinflunine versus alkylating agent in metastatic breast cancer. http://www.clinicaltrials.gov/ct2/show/NCT01091168?term=vinflunine+AND+breast+cancer&rank= 4&submit_fld_opt= Accessed 12 October 2012. 30 Campone M, Cortes-Funes H, Vorobiof D et al. Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy. British Journal of Cancer. 2006; 95: 1161-1166. 31 Fumoleau P, Cortes-Funes H, Taleb A et al. Phase 2 study of single-agent IV vinflunine as third- line treatment of metastatic breast cancer after failure of anthracycline-/taxane-based chemotherapy. American Journal of Clinical Oncology. 2009;32(4):375-380. 32 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 64. London: BMJ Group and RPS Publishing, September 2012.

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