Masitinib for Advanced Or Metastatic Malignant Melanoma with a C-Kit Juxtamembrane Mutation

Horizon Scanning Research January 2016 & Intelligence Centre

Masitinib for advanced or metastatic malignant melanoma with a c-kit juxtamembrane mutation

LAY SUMMARY

Melanoma is a type of skin cancer that can appear anywhere on the This briefing is based on body and usually begins with a mole. The back, legs and face are information commonly affected areas of the body. Melanoma is the fifth most available at the time common cancer in the UK with a third of people diagnosed under the of research and a age of 55. Treatment of melanoma is often successful at first, but may limited literature begin to fail as the cancer spreads and enters end-stage disease. search. It is not intended to be a Masitinib is a new drug for the treatment of melanoma which is given definitive statement as a tablet. Some studies have suggested masitinib may be helpful for on the safety, people whose melanoma has one particular type of genetic mutation efficacy or and whose disease has spread. More studies are now aiming to show effectiveness of the how well it works and that it is safe to use. health technology covered and should If masitinib is licensed for use in the UK, it could be a new treatment not be used for option that may improve survival in patients with end-stage disease. commercial purposes or commissioning NIHR HSRIC ID: 5780 without additional information.

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 Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

Malignant melanoma: unresectable or metastatic end stage disease; with c-Kit juxtamembrane mutation.

TECHNOLOGY

DESCRIPTION

Masitinib (AB1010, masitinib mesilate, masitinib mesylate) is a highly selective tyrosine kinase inhibitor that targets the c-Kit, Lyn and Fyn signalling pathways. By combined targeting of these different pathways, masitinib is particularly efficient in controlling mast cell survival, differentiation and degranulation1

In a phase III clinical trial, masitinib is administered orally at 7.5mg/kg daily.

Masitinib is currently being developed in 13 phase III indications; seven in oncology, three in inflammatory diseases, and three in neurodegenerative diseases. A range of phase II clinical trials are also ongoing, mainly in oncology.

Masitinib does not currently have any Marketing Authorisation in the EU for any indication.

INNOVATION and/or ADVANTAGES

If licensed, masitinib will provide an additional oral treatment option for patients with unresectable or metastatic end-stage malignant melanoma with c-Kit juxtamembrane mutation.

DEVELOPER

AB Science.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Malignant melanoma is a type of cancer that arises from melanocytes. It most commonly occurs in the skin, but can also be found in the uveal tract, upper digestive tract, anal canal, rectum and vagina2,3. Activating mutations and/or gene amplification of c-KIT have been found in 28% of cutaneous melanomas that arise in chronically sun damaged skin4. C-Kit mutations occur in a subgroup of cutaneous melanomas where the more likely mutation is BRAF, however they are more likely to occur in mucosal and acral melanomas, which are less likely to have BRAF mutations, and therefore pose an unmet need for new targeted therapiesa.

a Expert personal opinion.

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About half of all melanomas start with a change in previously normal-looking skin. As the abnormal melanocytes start to spread into the surrounding epidermis, they begin to look like a dark spot or mole (nevus) on the skin3. Other melanomas may develop from existing nevi. Signs of melanoma arising from previously existing nevi may include asymmetry, change of shape, change in colour and/or diameter, or an evolving appearance (including the area becoming raised or dome-shaped), itchiness, pain, bleeding or crustiness5,6. The main risk factor for developing melanoma is exposure to ultraviolet radiation from natural or artificial sources, e.g. the sun or sunbeds. People with very fair skin, sun-sensitive skin, large numbers of nevi, dysplastic nevi, reduced immunity, or a family history of malignant melanoma, have an increased risk of disease7. Metastatic melanoma describes disease which has spread to other parts of the body, most commonly the lungs, liver, brain, bones, or to distant lymph nodes or areas of the skin3.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011). • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Children, Teenagers and Young Adults). B12/S/b. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a.

CLINICAL NEED and BURDEN OF DISEASE

Over the last thirty years, rates of malignant melanoma in the UK have risen faster than any of the current ten most common cancers8. Around 13,500 new cases of malignant melanoma were diagnosed in 2012 in the UK8. More than one-third of all cases occur in people aged under 558. Malignant melanoma is almost twice as common in young women (up to 34 years of age) as in young men, but more men than women die from it8. The annual incidence of malignant melanoma is estimated at 0.02% in England, equating to 10,773 people9. At presentation, 10% of cutaneous melanomas are metastatic10; metastatic disease is associated with extremely poor survival with a median survival of 6-10 months11. Approximately 70% of people diagnosed with metastatic or unresectable melanoma may be suitable to receive chemotherapy and active therapy9. Somatic mutations in c-Kit have been found in 2-8% of all malignant melanoma12 though they are relatively more common in certain subgroups13,a.

In 2014-15, there were 15,820 hospital admissions for malignant melanoma of the skin (ICD- 10 C43), resulting in 12,500 bed days and 16,269 finished consultant episodes14. 2,237 deaths from malignant melanoma of the skin were registered in England and Wales during 2013 (ICD-10 C43)15.

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PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Melanoma (advanced and metastatic) – temozolomide [ID316]. Expected date of issue to be confirmed. • NICE technology appraisal in development. Melanoma (metastatic) – paclitaxel albumin- bound nanoparticles (1st line) [ID570]. Expected date of issue to be confirmed. • NICE technology appraisal in development. Melanoma (resected stage IV, high risk stage III) – ipilimumab (adjuvant) [ID721]. Expected date of issue to be confirmed. • NICE technology appraisal in development. Melanoma (BRAF V600, advanced, unresectable, metastatic) – cobimetinib (with vemurafenib) [ID815]. Expected October 2016. • NICE technology appraisal in development. Melanoma (untreated, advanced, unresectable, metastatic) – nivolumab (with ipilimumab) [ID848]. Expected September 2016. • NICE technology appraisal in development. Melanoma (BRAF V600E mutation positive, unresectable, metastatic) – dabrafenib and trametinib [ID661]. Expected August 2016. • NICE technology appraisal in development. Melanoma (metastatic) – talimogene laherparepvec [ID508]. Expected July 2016. • NICE technology appraisal in development. Melanoma (advanced, unresectable, metastatic) – nivolumab [ID845]. Expected May 2016. • NICE technology appraisal. Pembrolizumab for advanced melanoma not previously treated with ipilimumab (TA366). November 2015. • NICE technology appraisal. Pembrolizumab for treating advanced melanoma after disease progression with ipilimumab (TA357). October 2015. • NICE technology appraisal. Dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma (TA321). October 2014. • NICE technology appraisal. Ipilimumab for previously untreated advanced (unresectable or metastatic) melanoma (TA319). July 2014. • NICE technology appraisal. Vemurafenib for treating locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma (TA269). December 2012. • NICE technology appraisal. Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma (TA268). December 2012.

• NICE clinical guidelines. Melanoma: assessment and management (NG14). July 2015. • NICE clinical guidelines. Improving outcomes for people with skin tumours including melanoma (CSG8). May 2010. • NICE public health guidance. Skin cancer prevention: information, resources and environmental changes (PH32). January 2011.

Other Guidance

• American Society of Clinical Oncology. Sentinel lymph node biopsy for melanoma: ASCO and SSO joint clinical practice guideline. 201216. • European Society for Medical Oncology. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201217. • American Academy of Dermatology (AAD). Guidelines of care for the management of primary cutaneous melanoma. 201118.

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• British Association of Dermatologists. Revised UK guidelines for the management of cutaneous melanoma. 201019. • Royal College of Physicians. The prevention, diagnosis, referral and management of melanoma of the skin: concise guidelines. 200720. • Scottish Intercollegiate Guidelines Network (SIGN). Cutaneous melanoma: a national guideline. 200421.

CURRENT TREATMENT OPTIONS

Non-surgical modalities, including immunotherapy, chemotherapy, radiation therapy, or a combination of these treatments may be offered for inoperable stage III and IV disease (locally advanced or metastatic disease)22. Treatment options include23,24,25,26,27,28:

• Biological therapy: o Vemurafenib for inoperable stage III and IV BRAF mutant melanoma. o Dabrafenib for inoperable stage III and IV BRAF mutant melanoma. o Checkpoint inhibitors o Ipilimumab for unresectable stage III or IV malignant melanoma. o Pembrolizumab for unresectable stage III or IV malignant melanoma. • Chemotherapy – dacarbazine remains standard first line chemotherapy for wild-type BRAF melanoma, and is the most commonly used chemotherapy in the UK. Other options include: o Temozolomide. o Cisplatin or carboplatin. o Vinca alkaloids – vindesine. o Paclitaxel. o Nitrosoureas – carmustine. o Carboplatin and paclitaxel in combination. o Dacarbazine and a vinca alkaloid in combination. • Immunotherapy – interferon-alpha and interleukin-2. • Radiotherapy may be used to palliate locally advanced or metastatic disease where the main goal is symptom control or adjuvantly for high risk lymph node basins. Stereotactic radiosurgery may be offered for low volume oligometastatic brain metastasesb. • Surgery – excision of the primary tumour, affected lymph nodes and in transit recurrent disease. Metastasectomies. • Other: o Imiquimod for lentigo maligna. o Isolated limb perfusion – with melphalan, for recurrent disease within a limb. o Electrochemotherapy (with bleomycin) – palliative for recurring in-transit metastases and also for fungating lesions.

EFFICACY and SAFETY

Trial AB08026, NCT01280565; masitinib vs dacarbazine; phase III. Sponsor AB Science. Status Ongoing. Source of Trial registry29, manufacturer. information Location EU (not UK) and USA. Design Randomised, active-controlled.

b Expert personal opinion.

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Participants n=112; aged 18 years and older; histologically or cytologically confirmed non- resectable or metastatic stage III or stage IV melanoma; c-Kit juxtamembrane mutation confirmed by DNA or RNA sequencing; measurable disease according to RECIST; Eastern Cooperative Oncology Group (ECOG) performance score of ≤2. Schedule Randomised to oral masitinib 7.5mg/kg per day; or intravenous dacarbazine 1,000mg/m2 once every 3 weeks. Follow-up Active treatment period 24 weeks or until disease progression without clinical benefit, limiting toxicity or patient consent withdrawal. Follow-up of patients exiting the study for tumour progression or toxicity, every 12 weeks until death. Primary Objective response rate. outcome Secondary Overall progression-free survival, overall survival, ECOG performance status, outcomes EORTC QLQ-C30c. Expected Primary completion date reported as December 2017. reporting date

ESTIMATED COST and IMPACT

COST

The cost of masitinib is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

Impact on Health and Social Care 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 and Other Resource Use

 Increased drug treatment costs: likely to be  Reduced drug treatment costs more expensive than dacarbazine. The relative cost-effectiveness of masitinib compared to ipilimumab or pembrolizumab would be of interestd.

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

 Other:  None identified

c The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. d Expert personal opinion.

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Other Issues

 Clinical uncertainty or other research question  None identified identified: a lot of the literature looking at Kit inhibition in melanoma suggest that the mutation type does not reliably predict response. This needs to be considered in further detaile.

REFERENCES

1 Dubreuil P, Letard S, Ciufolini M et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One 2009;4(9):e7258. 2 Sasse A. D, Sasse EC, Clark LG et al. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma (Review). Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD005413. DOI: 10.1002/14651858.C 3 Macmillan. Types of melanoma. April 2014. www.macmillan.org .uk/Cancerinformation/Cancertypes/Melanoma/AboutMelanoma/Typesofmelanoma.aspx Accessed 7 December 2015. 4 Curtin JA, Busam K, Pinkel D et al. Somatic activation of KIT in distinct subtypes of melanoma. Journal of Clinical Oncology 2006;24(26):4340-4346. 5 Macmillan. Symptoms of melanoma. April 2014. www.macmillan.org.uk/Cancerinformation/Cancertypes/Melanoma/Symptomsanddiagnosis/Sympt omsofmelanoma/Symptomsofmelanoma.aspx Accessed 7 December 2015. 6 Cancer Research UK. Melanoma symptoms. October 2014. www.cancerresearchuk.org/about- cancer/type/melanoma/about/melanoma-symptoms Accessed 7 December 2015. 7 Macmillan. Risk factors and causes of melanoma. April 2014. www.macmillan.org.uk/Cancerinformation/Cancertypes/Melanoma/AboutMelanoma/Riskfactorsan dcauses.aspx Accessed 7 December 2015. 8 Cancer Research UK. Skin cancer statistics. www.cancerresearchuk.org/healthprofessional/cancer-statistics/statistics-by-cancer-type/skin-cancer#heading-Zero Accessed 20 January 2016. 9 National Institute for Health and Clinical Excellence. Costing statement: Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma. Technology appraisal TA268. London: NICE; December 2012. 10 National Institute for Health and Clinical Excellence. Vemurafenib for treating locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma. Technology appraisal TA269. London: NICE; December 2012. 11 Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. New England Journal of Medicine 2012;366(8):707-714. 12 My Cancer Genome. KIT in melanoma. www.mycancergenome.org/content/disease/melanoma/kit/110/ Accessed 9 December 2015. 13 Beadling C, Jacobson-Dunlop E, Hodi FS et al. KITgene mutations and copy number in melanoma subtypes. Clinical Cancer Research 2008;14:6821. 14 Health and Social Care Information Centre, Hospital Episode Statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk 15 Office for National Statistics. Deaths registered in England and Wales (series DR) - 2014. www.ons.gov.uk 16 Wong SL, Balch CM, Hurley P et al. Sentinel lymph node biopsy for melanoma: ASCO and SSO joint clinical practice guideline. Journal of Clinical Oncology 2012;30(23):2912-2918. 17 Dummer R, Hauschild A, Guggenheim M et al. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23:(Supplement 7):vii86-vii91. 18 Bichakjian CK, Halpern AC, Johnson TM et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. Journal of the American Academy of Dermatology 2011:65(5);1032-47.

e Expert personal opinion.

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19 Marsden JR, Newton-Bishop JA, Burrows L et al. Revised UK guidelines for the management of cutaneous melanoma 2010. British Journal of Dermatology 2010;163(12):238-256. 20 Newton-Bishop JA, Bataille V, Gavin A et al. The prevention, diagnosis, referral and management of melanoma of the skin: concise guideline. Clinical Medicine 2007:7;283-290. 21 Scottish Intercollegiate Guidelines Network. Cutaneous melanoma. National clinical guideline 72. Edinburgh: SIGN; February 2004 (update). 22 Cancer Research UK. Advanced melanoma (stage 4). January 2014. www.cancerresearchuk.org/about-cancer/type/melanoma/treatment/advanced-melanoma#bio Accessed 8 December 2015. 23 National Institute for Health and Clinical Excellence. Vemurafenib for treating locally advanced or metastatic BRAF V600 mutation-positive malignant melanoma. Technology appraisal TA269. London: NICE; December 2012. 24 National Institute for Health and Clinical Excellence. Ipilimumab for previously treated advanced (unresectable or metastatic) melanoma. Technology appraisal TA268. London: NICE; December 2012. 25 National Institute for Health and Care Excellence. Skin cancer prevention: information, resources and environmental changes. Public health guidance PH32. London: NICE; January 2011. 26 NHS Choices. Skin cancer (melanoma). www.nhs.uk/Conditions/Malignant- melanoma/Pages/Treatment.aspx Accessed 8 December 2015. 27 National Cancer Institute at the National Institutes of Health. Melanoma Treatment (PDQ). www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/page8#Section_382 Accessed 8 December 2015. 28 National Institute for Health Research Horizon Scanning Centre. Vemurafenib and bovimetinib for previously untreated BRAFV600-mutation positive, unresectable, locally advanced or metastatic melanoma – first line. University of Birmingham, July 2014. www.hsc.nihr.ac.uk 29 ClinicalTrials.gov. A phase 3 study to compare efficacy and safety of masitinib to dacarbazine in the treatment of patients with non-resectable or metastatic stage 3 or stage 4 melanoma carrying a mutation in the juxta membrane domain of C-Kit. clinicaltrials.gov/ct2/show/NCT01280565 Accessed 8 December 2015.