Farletuzumab for ovarian cancer

April 2012

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 NIHR Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

April 2012

Farletuzumab for ovarian cancer

Target group • Ovarian cancer: relapsed, platinum-sensitive – in combination with carboplatin and a taxane.

Background Primary ovarian, fallopian and peritoneal cancers arise from the epithelial tissues of the abdomen, fallopian tubes and ovaries. Almost 90% of adult ovarian tumours are epithelial cancers. Regardless of its origin, ovarian cancer leads to similar symptoms and is treated in a similar way1. At the time of diagnosis 60% of patients will have FIGOa stage III disease (peritoneal metastasis) and 10% will have disease in the liver or outside of the abdomen and pelvis (stage IV); stage III/IV disease is treatable but largely incurable. The remainder have disease confined to the ovaries (stage I) and/or pelvis (stage II), where cure is a realistic goal of treatmenta.

Technology description Farletuzumab (MORAb-003) is a humanised IgG1 monoclonal antibody that selectively targets folate receptor alpha. Expression is highly restricted in normal adult tissues but upregulated in a wide range of human cancer types, including epithelial ovarian cancer. In vitro, farletuzumab inhibits folate receptor alpha-dependent cell growth and mediates tumour cytotoxicity through complement-dependent and antibody-dependent mechanisms. In addition, there is evidence that farletuzumab reduces tumour growth through inhibition of folate receptor alpha-mediated lyn kinase phosphorylation2. Farletuzumab is administered via intravenous (IV) infusion at 1.25mg/kg or 2.5mg/kg once weekly for three weeks in combination with carboplatin and a taxane.

Farletuzumab is also in a phase II trial for non-small cell lung cancer.

Innovation and/or advantages If licensed for this indication, farletuzumab would provide a new treatment option for this patient group.

Developer Eisai Ltd.

Availability, launch or marketing dates, and licensing plans In phase III clinical trials.

NHS or Government priority area This topic is relevant to Improving Outcomes: A Strategy for Cancer (2011).

Relevant guidance • NICE technology appraisal in development. Ovarian, fallopian tube and primary peritoneal cancer (recurrent, advanced, platinum-sensitive, partially platinum- sensitive) – bevacizumab. Expected February 20133. • NICE technology appraisal in development. Ovarian cancer (metastatic) – bevacizumab (with paclitaxel and carboplatin). Expected July 20124.

a FIGO – International Federation of Obstetricians and Gynaecologists staging for ovarian cancer. 2 April 2012

• NICE technology appraisal. Trabectedin for the treatment of relapsed ovarian cancer. 20115. • NICE technology appraisal. Paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer. 20056. • NICE technology appraisal. Guidance on the use of paclitaxel in the treatment of ovarian cancer. 20037. • NICE clinical guideline. The recognition and initial management of ovarian cancer. 20118.

• European Society for Medical Oncology. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 20109. • SIGN. Epithelial ovarian cancer. 200310.

Clinical need and burden of disease Ovarian cancer is the fifth most common cancer in women in the UK11 with an overall 5- year survival rate of 38.2%12. Most women (approximately 75%)13 present with advanced disease and undergo debulking surgery followed by 6 cycles of platinum-based chemotherapy14. Although most patients respond to initial treatment, up to 70% with advanced-stage ovarian cancer subsequently develop recurrent disease15. The median time to progression after primary treatment (surgery and chemotherapy) is 15-18 monthsb, and the median overall survival in patients with advanced ovarian cancer is 31- 51 months16.

The highest incidence rates occur in women aged 50 and over, with approximately 80% of cases occurring in this age group17. In 2008, there were 5,704 new cases registered for ovarian cancer17 and 3,676 deaths in England and Wales in 201018. In England, there were 37,898 admissions for ovarian, fallopian tube and peritoneal cancer (ICD C56, C57 and C48 respectively) resulting in 86,674 bed days and 40,611 finished consultant episodes in 2010-1119.

Existing comparators and treatments First line chemotherapy is invariably a platinum-based therapy alone or in combination with paclitaxel. For recurrent ovarian cancer, current chemotherapy options include14,20: • Gemcitabine. • Liposomal doxorubicin. • Paclitaxel alone. • Topotecan (not widely used)c. • Trabectedin (not widely used)c.

Efficacy and safety

Trial MORAb-003-004, NCT00849667; MORAb-003-002, NCT00318370; farletuzumab vs placebo; phase III. farletuzumab alone vs farletuzumab in combination with carboplatin and a taxane; phase II. Sponsor Morphotek. Morphotek. Status Ongoing. Complete and published in abstract.

b Expert personal communication. 3 April 2012

Source of Trial registry21. Abstract22, trial registry23 and company. information Location EU (inc UK), USA, Canada and other EU and USA. countries. Design Randomised, placebo-controlled. Non-randomised. Participants n=1,080 (planned); adults; histologically n=58; adults; histologically confirmed and schedule or cytologically confirmed diagnosis of platinum-sensitive, non-mucinous non-mucinous epithelial ovarian cancer epithelial ovarian cancer including including primary peritoneal or fallopian fallopian tube and primary peritoneal tube malignancies. cancer; first relapse after remission of 6 Randomised to IV farletuzumab to 18 months. 1.25mg/kg, 2.5mg/kg or placebo once Both treatment groups receive IV weekly until disease progression. farletuzumab 100mg/m2 once weekly All treatment groups also receive IV for three weeks. One treatment group taxane (paclitaxel 175mg/m2 or docetaxel also receive IV paclitaxel 175mg/m2 or 75mg/m2) plus carboplatin (area under IV docetaxel 75mg/m2 plus carboplatin concentration-time curve) on day 1 of a (area under the concentration-time 21 day cycle for approximately 6 cycles. curve) on day 1 of a 21 day cycle for approximately 6 cycles.

Follow-up Active treatment until disease Active treatment until disease progression. progression. Subjects with partial or complete response receive single agent farletuzumab maintenance therapy in extension study NCT01018563 . Primary Progression-free survival (PFS). Serologic response (CA-125). outcome Secondary Overall survival; cancer antigen 125 Time to serologic response; duration of outcome (CA-125) PFS; Gynaecologic Cancer serologic response; overall response InterGroup (GCIG) PFS; length of first rate; PFS; percentage with prolongation vs second remission; tumour response; of remission. serologic response (CA-125); quality of life; resource utilisation; pharmacokinetic drug-drug interaction (PK DDI) sub- study. Key results - For the farletuzumab plus chemotherapy group (n=47), 87% achieved a 50% or greater reduction in CA-125 levels based on GCIG criteria, measured by response evaluation criteria in solid tumours (RECIST) scores. 6.8% achieved a complete response, 63.6% achieved a partial response and 20.5% had stable disease. 10 out of 39 subjects evaluated also achieved prolongation of response. Patients receiving single agent farletuzumab were reported to have shown transient responses of CA-125 only. Adverse effects - Few drug-related AEs were reported. (AEs) Expected Estimated primary completion date Mar - reporting date 2013.

4 April 2012

Trial NCT01018563, MORAb-003-0002A; farletuzumab; phase II extension. Sponsor Morphotek. Status Ongoing. Source of Trial registry24. information Location EU and USA. Design Single arm. Participants and n=3 (planned); adults; normalisation of CA-125 levels or complete or total schedule response after farletuzumab and chemotherapy received in trial NCT00318370; no disease progression during participation in trial NCT00318370. Patients receive maintenance infusions of farletuzumab 300mg/m2 once every 3 weeks. Follow-up Patients may continue with study as long as investigator feels they are deriving clinical benefit. Primary outcome CA-125 level. Secondary RECIST scores. outcome Expected Previously reported as Dec 2011. As of April 2012, all 3 subjects remain active reporting date in the study.

Estimated cost and cost impact The cost of farletuzumab is not yet known. The costs of other selected treatments for ovarian cancer are25:

Drug Dose Cost per cyclec Pegylated liposomal 40mg/m2 IV once a month. £1,073 doxorubicin (PLD) (Caelyx) Topotecan 4mg/m2 IV on days 1, 8 and 15 of a 28 day £1,744 cycle. Paclitaxel 80mg/m2 IV on days 1, 8 and 15 of a 28 day £902 cycle.

Claimed or potential impact – speculative

Patients  Reduced mortality or increased  Reduction in associated Quicker, earlier or more accurate length of survival morbidity or improved quality of diagnosis or identification of life for patients and/or carers disease Other: None identified

Services  Increased use: weekly IV Service organisation Staff requirements administration. Decreased use Other: None identified

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed  New costs: new additional Savings: Other: treatment option. c Based on average surface area 1.7m2. 5 April 2012

Other issues Clinical uncertainty or other research question identified:  None identified

References

1 Cancer Research UK. Ovarian cancer http://cancerhelp.cancerresearchuk.org/type/ovarian-cancer/ Accessed 19 March 2012. 2 Konner JA, Bell-McGuinn KM, Sabbatini P et al. Farletuzumab, a humanised monoclonal antibody against folate receptor α, in epithelial ovarian cancer: a phase I study. Clinical Cancer Research 2010;16:5288-5295. 3 National Institute for Health and Clinical Exellence. Ovarian, fallopian tube and primary peritoneal cancer (recurrent, advanced, platinum-sensitive, partially platinum-sensitive) – bevacizumab. Technology appraisal in development. Expected February 2013. 4 National Institute for Health and Clinical Exellence. Ovarian cancer (metastatic) – bevacizumab (with paclitaxel and carboplatin). Technology appraisal in development. Expected July 2012. 5 National Institute for Health and Clinical Excellence. Trabectedin for the treatment of relapsed ovarian cancer. Technology appraisal TA222. London: NICE; April 2011 6 National Institute for Health and Clinical Excellence. Paclitaxel, pegylated liposomal doxorubicin hydrochloride and topotecan for second-line or subsequent treatment of advanced ovarian cancer. Technology appraisal TA91. London: NICE; May 2005. 7 National Institute for Health and Clinical Excellence. Guidance on the use of paclitaxel in the treatment of ovarian cancer. Technology appraisal TA55. London: NICE; January 2003. 8 National Institute for Health and Clinical Excellence. The recognition and initial management of ovarian cancer. Clinical guideline CG122. London: NICE; April 2011. 9 Colombo N, Peiretti M, Parma G et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21 suppl 5: v23- v30. 10 Scottish Intercollegiate National Guidelines. Epithelial ovarian cancer. Clinical guideline 75. October 2003. 11 Cancer Research UK. Ovarian cancer statistics – Key Facts http://info.cancerresearchuk.org/cancerstats/types/ovary/uk-ovarian-cancer-statistics Accessed 19 March 2012. 12 Rachet B, Maringe C, Nur U et al. Population-based cancer survival trends in England and Wales up to 2007: an assessment of the NHS cancer plan for England. Lancet Oncology 2009;10(4):351-369. 13 Martinek IE, Kehoe S. When should cytoreduction in advanced ovarian cancer take place? Journal of Oncology 2010:2010; Article ID 852028. 14 Morgan Jr RJ, Alvarez RD, Armstrong DK et al. Ovarian cancer. Clinical practice guidelines in oncology. The Journal of the National Comprehensive Cancer Network. 2008;6:766-794. 15 Herzog TJ and Pothuri B. Ovarian cancer: a focus on management of recurrent disease. Nature Clinical Practice Oncology. 2006;3:604-611. 16 Friedlander M, Hannock KC, Rischin D et al. A phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynaecologic Oncology. 2010;119:32-37. 17 Cancer Research UK. Ovarian cancer – UK incidence statistics http://info.cancerresearchuk.org/cancerstats/types/ovary/incidence/ Accessed 19 March 2012. 18 Office for National Statistics. Mortality statistics deaths registered in 2010, series DR 2010 www.statistics.gov.uk 19 NHS. Hospital episode statistics. NHS England 2010-11. HES data 2011. www.hesonline.nhs.uk 20 Cancer Research UK. Ovarian cancer symptoms, diagnosis and treatment http://info.cancerresearchuk.org/cancerstats/types/ovary/symptoms/ Accessed 19 March 2012. 21 ClinicalTrials.gov. Efficacy and safety of MORAb-003 in subjects with platinum-sensitive ovarian cancer in first relapse http://clinicaltrials.gov/ct2/show/NCT00849667?term=NCT00849667&rank=1 Accessed 19 March 2012. 22 Armstrong DK, Bicher A, Coleman RL et al. Exploratory phase II efficacy study of MORAb-003, a monoclonal antibody against folate receptor alpha, in platinum-sensitive ovarian cancer in first relapse. Journal of Clinical Oncology (Meeting Abstracts) 2008;26 suppl 15: 5500. 23 ClinicalTrials.gov. Effectiveness of MORAb-003 in women with ovarian cancer who have relapsed after platinum-based chemotherapy http://clinicaltrials.gov/ct2/show/NCT00318370 Accessed 20 March 2012. 24 ClinicalTrials.gov. An open label extension study of the efficacy of MORAb-003 http://www.clinicaltrials.gov/ct2/show/NCT01018563?term=MORAb-003&rank=1 Accessed 21 March 2012. 25 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary BNF 63. London: BMJ Group and RPS Publishing, March 2012.

6 April 2012

The National Institute for Health Research Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

The NIHR Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon

7