Horizon Scanning Centre November Vinflunine (Javlor) monotherapy for advanced breast cancer SUMMARY NIHR HSC ID: 7887

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1 Horizon Scanning Centre November 2012 Vinflunine (Javlor) monotherapy for advanced breast cancer SUMMARY NIHR HSC ID: 7887 This briefing 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 or i i i 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 vincaalkaloid derivative which acts as a microtubule inhibitor and is currently licensed for the treatment of adults with metastatic bladder cancer. 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 year. In the UK, 48,788 new cases (male and female) were diagnosed in 2009 and 11,633 deaths occurred in Breast cancer risk is strongly related to age, with 81% of cases occurring in women aged over 50 years. An estimated 5% of women have metastases at diagnosis and a further 35% will go on to develop them over the following 10 years. Five year survival rates for women with stage III breast cancer is around 50%, however this decreases to approximately 13% with stage IV disease. The aim of treatment for advanced breast cancer is to ameliorate symptoms, maintain quality of life and prolong survival. Treatment options include several chemotherapy agents, given either as monotherapy or in combination. Vinflunine is in a phase III clinical trial comparing its effect on overall survival against treatment with alkylating agents. This trial is expected to complete in 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 nihrhsc@contacts.bham.ac.uk Web:

2 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 microtubules and decreases their growth rate 1. Microtubules play a key role in mitosis and inhibitors suppress the microtubule dynamics required for proper mitotic function, effectively blocking cell cycle progression and resulting in apoptosis 1. MTIs, such as taxanes, 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/m 2 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 fatigue 2. 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 ducts 3. 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 2

3 presence of disease at distant sites. The most common sites for metastases are the lymph nodes, bone, liver, lungs and brain 4. 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 year 5,6. In the UK, 48,788 new cases (male and female) were diagnosed in and 11,633 deaths occurred in 2010, accounting for around 15% of all female deaths from cancer 7. In , 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 groups 5. Analysis of breast cancer survival by level of deprivation has consistently shown higher survival for more affluent women 5. An estimated 5% of women have metastases at diagnosis and a further 35% will develop them over the following 10 years 9. 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 metastases 10. Five year survival rates for women with stage III breast cancer is around 50%, however this decreases to approximately 13% with stage IV disease 11. 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 NICE technology appraisal. Bevacizumab in combination with capecitabine for the firstline treatment of metastatic breast cancer (TA263). August 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 NICE technology appraisal. Eribulin for the treatment of locally advanced or metastatic breast cancer (TA250). April NICE technology appraisal. Fulvestrant for the treatment of locally advanced or metastatic breast cancer (TA239). December NICE technology appraisal. Bevacizumab in combination with a taxane for the first line treatment of metastatic breast cancer (TA214). February NICE technology appraisal. Gemcitabine for the treatment of metastatic breast cancer (TA116). January NICE technology appraisal. Guidance on the use of trastuzumab for the treatment of advanced breast cancer (TA34). March

4 NICE clinical guideline. Advanced breast cancer diagnosis and treatment (CG81). February NICE clinical guideline. Breast cancer (early & locally advanced): diagnosis and treatment (CG80). February 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 NICE quality standard. Breast cancer (QS12). September NICE cancer service guidance. Improving outcomes in breast cancer (CSGBC). August Other Guidance European Society for Medical Oncology. Locally recurrent or metastatic breast cancer. Clinical practice guidelines for diagnosis, treatment and follow-up SIGN. Management of breast cancer in women Cancer Services Collaborative Improvement Partnership. Breast cancer service improvement guide 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 include 9,20,27 : Surgery, if appropriate. Radiotherapy for local control and painful bone metastases. Standard chemotherapy regimens: For patients who have not received adjuvant chemotherapy a : o 5-Fluorouracil, epirubicin and cyclophosphamide (FEC). o Doxorubicin and cyclophosphamide (AC). For patients not suitable for treatment with anthracyclines (FEC or AC) because they are contraindicated or because they have received prior anthracycline treatment in the adjuvant or metastatic setting, NICE recommends 9 : o Docetaxel as first line expert opinion suggests paclitaxel, nabpaclitaxel or paclitaxel with gemcitabine are also used first-line b. o Vinorelbine or capecitabine as second line expert opinion suggests capecitabine is the usual second line option in UK practice b. o Capecitabine or vinorelbine as third line expert opinion suggests vinorelbine is the usual third line option in UK practice b (following anthracycline, taxoid and capecitabine therapy 28 ). 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 vinorelbine b. Combination therapy may be considered for those with more aggressive disease: o Doxetaxel with capecitabine. a Expert personal communication. 4

5 o Gemcitabine with paclitaxel recommended by NICE for metastatic breast cancer only when docetaxel or docetaxel with capecitabine are considered appropriate. o Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) rarely used b. 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 Sponsor Status Source of information Location Design Participants Schedule Follow-up Primary outcome Secondary outcomes Expected reporting date NCT , EUCTR FR; vinflunine vs alkylating agent; phase III. Pierre Fabre Medicament. Ongoing. Trial registry 29. EU (incl UK) and other countries. Randomised, active-controlled. n=594 (planned); aged years; females; breast cancer; metastatic; 2 prior chemotherapy regimens including anthracyclines, taxanes, antimetabolite and vincaalkaloids, and are no longer candidates for these drugs. Randomised to vinflunine 280mg/m 2 IV on day 1 of a 21 day cycle; or an alkylating agent of physician choice, including cyclophosphamide, melphalan, mitomycin c, thiotepa, cisplatin or carboplatin. Active treatment continues until disease progression or unacceptable toxicity; then follow-up every month for 6 months, then every 3 months until death. Overall survival. Tumour response rate; progression free survival; quality of life; adverse events. Estimated study completion date Q Trial Vinflunine; phase II. Vinflunine; phase II. Sponsor Investigator led. Investigator led. Status Complete and published. Complete and published. Source of Publication 30. Abstract 31. 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 cancer; advanced or metastatic; received prior anthracycline/taxane based therapy. n=56; females; breast cancer; metastatic; following failure of anthracycline-based and taxane-based chemotherapy. Schedule Vinflunine 320mg/m 2 IV every 21 days. Vinflunine 320mg/m 2 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 outcomes Duration of response; progression free survival (PFS); overall survival (OS). Duration of response; PFS; OS. b Expert personal communication. 5

6 Key results Objective response, 18 out of 60 patients (response rate 30%); median duration of response, 4.8 months (95% CI ); median PFS, 3.7 months (95% CI ); median OS, 14.3 months (95% CI ). Adverse effects (AEs) Most common AEs included anaemia (83.3%), leucopenia (91.7%), neutropenia (91.7%), constipation (63.3%), nausea (58.3%), vomiting (46.7%) and fatigue (81.7%). Grade 3-4 leucopenia was experienced by 40% patients and grade 3-4 neutropenia occurred in 65% of patients. For treated and evaluable populations respectively: response rate, 12.5% and 14%; disease control rate, 42.9% and 51.2%; median PFS, 2.6 months (95%CI ); median OS, 11.4 months (95% CI ); duration of response, 6.8 months (95% CI 5.6-upper limit not reached). Grade 3-4 leucopenia was reported in 49.1%. Grade 3 neutropenia was reported in 30.9% of patients and grade 4 in 40% of patients. Other grade 3 toxicities included anaemia (5.5%), fatigue (14.3%) and constipation (7.1%). ESTIMATED COST and IMPACT COST Vinflunine is already marketed in the UK for the treatment of metastatic bladder cancer; 250mg (10ml vial) costs 1, and 50mg (2ml vial) costs Treatment with 280mg/m 2 for one cycle would cost 2, c,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 identified: there are already a significant number of agents which are used in this setting and UK practice d. c Based on average body surface area of 1.88m 2. d Expert personal communication. None identified 6

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8 22 National institute for Health and clinical excellence. Breast cancer quality service. QS12. London: NICE; September National Institute for Health and Clinical Excellence. Improving outcomes in breast cancer. Cancer service guidance CSGBC. London: NICE; August 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): Scottish Intercollegiate Guidelines Network. Management of breast cancer in women. Clinical guideline No. 84. Edinburgh: SIGN; December Cancer Services Collaborative Improvement Partnership. Breast cancer service improvement guide. October Macmillan Cancer Support. Treating breast cancer. gbreastcancer.aspx Accessed 10 October NIHR Horizon Scanning Centre. Vinflunine (Javlor) with capecitabine for advanced breast cancer. Birmigham: NIHR HSC; June ClinicalTrials.gov. Trial of vinflunine versus alkylating agent in metastatic breast cancer. 4&submit_fld_opt= Accessed 12 October 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: Fumoleau P, Cortes-Funes H, Taleb A et al. Phase 2 study of single-agent IV vinflunine as thirdline treatment of metastatic breast cancer after failure of anthracycline-/taxane-based chemotherapy. American Journal of Clinical Oncology. 2009;32(4): British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 64. London: BMJ Group and RPS Publishing, September