Masitinib for Gastrointestinal Stromal Tumours – Second Line June 2012

Masitinib for gastrointestinal stromal tumours – second line

June 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.

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June 2012

Masitinib for gastrointestinal stromal tumours – second line

Target group • Gastrointestinal stromal tumours (GIST): unresectable and/or metastatic – second line, after progression with imatinib.

Technology description Masitinib (AB-1010; masitinib mesylate) is an orally active tyrosine kinase inhibitor which selectively inhibits the stem cell factor receptor (c-Kit), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and to a lesser extent focal adhesion kinase (FAK). It also inhibits mast cell degranulation. About 95% of GIST are positive for c-Kit expression, and 85%–90% of GIST have a gain-of-function mutation of either c-Kit or PDGFRα1. Masitinib is intended to substitute sunitinib for the second-line treatment of patients with unresectable and/or metastatic GIST that has progressed despite imatinib. It is administered orally at 12mg/kg/day, in a divided dose taken twice daily.

Masitinib is in phase III clinical trials for the treatment of asthma, malignant melanoma, mastocytosis, multiple myeloma and pancreatic cancer. It is also in phase II/III clinical trials for the treatment of multiple sclerosis and rheumatoid arthritis, and phase II clinical trials for Alzheimer’s disease.

Innovation and/or advantages If licensed, masitinib would provide an additional treatment option for this patient group whose therapeutic options are limited.

Developer AB Science.

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

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

Relevant guidance • NICE technology appraisal. Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours. Part review of NICE technology appraisal guidance 86. 20102. • NICE technology appraisal. Imatinib for the adjuvant treatment of gastrointestinal stromal tumours. 20103. • NICE technology appraisal. Sunitinib for the treatment of gastrointestinal stromal tumours. 20094. • NICE technology appraisal. Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. 20045.

• Allum WH, Blazeby JM, Griffin SM et al. Guidelines for the management of oesophageal and gastric cancer. 20116. • Reid R, O’Dywer P, MacDuff E et al. Guidelines for the management of gastrointestinal stromal tumours (GIST) in Scotland. 20097. 8 • SIGN clinical guideline. Management of oesophageal and gastric cancer. 2006 .

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• Association of Upper Gastrointestinal Surgeons of GB & Ireland. Guidelines for the management of gastrointestinal stromal tumours (GIST). 20059.

Clinical need and burden of disease Gastrointestinal stromal tumours are the most common mesenchymal tumours of the gastrointestinal (GI) tract, expressing the proto-oncogene protein CD117 (also known as c-Kit)10. GIST can occur anywhere in the GI tract, but the majority arise in the stomach (60–70%) and small bowel (25–35%)5. Although GIST can occur at any age, the mean age of presentation is between 50 and 70 years10. Many people with GIST are asymptomatic during early stages of the disease, but once tumours reach a large size they may rupture and bleed or obstruct the GI tract2. Prognosis depends on the resectability of the tumour10. Approximately half of new cases of GIST are likely to be unresectable and/or metastatic on first presentation2. Ten-year survival for resectable/non-metastatic tumours is 30-50%10, but prognosis for people with unresectable and/or metastatic GIST is poor, with few, if any people surviving beyond 5 years5.

GIST is rare cancer and accounts for less than 1% of all cancers of the GI tract10. The annual incidence of GIST is estimated to be around 15 per million, which equates to approximately 900 new cases per year in the UK7. The number of new cases of unresectable and/or metastatic GIST is estimated to be around 240 people per year11. Approximately 30-50 patients experience primary resistance to imatinib, and around 60- 100 patients develop a reduced response at a later stage11. Following failed imatinib treatment and in the absence of further treatment, survival is usually less than 1 year11. Sunitinib therapy is also limited by the development of secondary resistance12.

Existing comparators and treatments Surgical resection is the treatment of choice for resectable GIST10. Imatinib is licensed but not recommended by NICE for the adjuvant treatment of patients with GIST, who are at significant risk of relapse after surgery3,10. Surgery for advanced or metastatic GIST is not recommended unless there is an immediate clinical need2. Advanced or metastatic GIST is resistant to conventional cytotoxic chemotherapy and radiotherapy5.

NICE guidelines recommend4,5: • Imatinib 400mg/day for the first line treatment of people with unresectable and/or metastatic GIST. • Sunitinib for the second line treatment of people with unresectable and/or metastatic GIST, resistant or intolerant to imatinib.

Efficacy and safety

Trial NCT01506336, AB07001; masitinib or sunitinib; phase II. Sponsor AB Science. Status Ongoing. Source of information Trial registry13, manufacturer14. Location France. Design Randomised, active-controlled. Participants and schedule n=44; adults; histological proven GIST; c-Kit positive; metastatic or locally advanced; non-operable; resistant to imatinib at 400mg to 800mg per day. Randomised to masitinib at 12mg/kg/day or sunitinib at 50mg/day. Follow-up Active treatment until disease progression. Primary outcome Overall progression free survival.

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Secondary outcome Overall survival. Key results After 17 months median follow-up, the updated median overall survival was not reached for masitinib versus 16 months for sunitinib (Hazard Ratio: 0.27 [95% CI, 0.09-0.78]). After 18 months, 82% [95% CI, 59%- 93%] of patients treated with masitinib were still alive versus 33% [95% CI, 8%-62%] for patients treated with sunitinib. Adverse effects (AEs) Most common AEs observed in masitinib group were nausea/vomiting, diarrhoea and asthenia. Patients receiving masitinib experienced longer safety event free survival (p≤0.001) and a lower occurrence of severe AEs. Masitinib was well tolerated, with 17% of patients reporting treatment related grade 3 AEs, and no treatment related grade 4 AEs. Expected reporting date Study expected to complete by December 2012.

Estimated cost and cost impact The cost of masitinib is not yet known. The cost of sunitinib (Sutent, Pfizer) at 50mg once daily is around £3138.80 for 28 days15.

Claimed or potential impact – speculative

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

Services Increased use Service organisation Staff requirements

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: Savings:  Other: uncertain unit cost compared to comparator

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

References

1 Le Cesne A, Blay J-Y, Bui BN et al. A phase II study of oral masitinib mesylate in imatinib-naive patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST). European Journal of Cancer 2010;46:1344-1351. 2 National Institute for Health and Clinical Excellence. Imatinib for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours. Part review of NICE technology appraisal guidance 86. Technology appraisal TA209. London: NICE; November 2010. 3 National Institute for Health and Clinical Excellence. Imatinib for the adjuvant treatment of gastrointestinal stromal tumours. Technology appraisal TA196. London: NICE; August 2010. 4 National Institute for Health and Clinical Excellence. Sunitinib for the treatment of gastrointestinal stromal tumours. Technology appraisal TA179. London: NICE; September 2009. 5 National Institute for Health and Clinical Excellence. Imatinib for the treatment of unresectable and/or metastatic gastro-intestinal stromal tumours. Technology appraisal TA86. London: NICE; October 2004. 6 Allum WH, Blazeby JM, Griffin SM et al. Guidelines for the management of oesophageal and gastric cancer. GUT 2011;60:1449-1472.

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7 Reid R, O’Dywer P, MacDuff E et al. Guidelines for the management of gastrointestinal stromal tumours (GIST) in Scotland. November 2009. http://www.pathologyscotland.org/download/sgpg/guidelines/gist.pdf Accessed on 2 May 2012. 8 Scottish Intercollegiate Guidelines Network. Management of oesophageal and gastric cancer. National clinical guideline 87. Edinburgh: SIGN; June 2006. 9Association of Upper Gastrointestinal Surgeons of GB & Ireland. Guidelines for the management of gastrointestinal stromal tumours (GIST). Care Guideline. July 2005. 10 Hislop J, Quayyum Z, Elders A et al. Clinical effectiveness and cost effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: a systematic review and economic evaluation review and economic evaluation. Health Technology Assessment 2011;15(25). 11 National Institute for Health and Clinical Excellence. Final scope for the appraisal of sunitinib for the treatment of gastrointestinal stromal tumours, London: NICE; August 2008. 12 Wang WL, Conley A, Reynoso D et al. Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumors. Cancer Chemotherapy and Pharmacology 2011;67 (Suppl 1):S15–S24. 13ClinicalTrials.gov. Masitinib in gastro-intestinal stromal tumor (GIST) resistant to imatinib. http://clinicaltrials.gov/ct2/show/NCT01506336?term=NCT01506336&rank=1 Accessed on 2 May 2012. 14Bloomberg.com. AB Science reports positive clinical study data: masitinib significantly extends overall survival as compared to Pfizer’s sutent in gleevec resistant GIST. February 2012. http://origin- www.bloomberg.com/apps/news?pid=conewsstory&tkr=PFE:GR&sid=aCr3ISWItgj4 Accessed on 2 May 2012. 15 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 61. London: BMJ Group and RPS Publishing, March 2012.

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