Horizon Scanning Research January 2016 & Intelligence Centre

Selumetinib with radioactive iodine therapy for differentiated thyroid cancer – first line

LAY SUMMARY

There are four different types of thyroid cancer, and the most common is known as differentiated thyroid cancer. It is a type of cancer which usually develops very slowly, and can often be cured by surgery. This briefing is based on However, in a small number of patients the cancer then returns and information becomes difficult to treat. Radioactive iodine therapy is often used available at the time after surgery to reduce the chance of the cancer returning. of research and a limited literature Selumetinib is a new drug for the treatment of thyroid cancer given as search. It is not a tablet twice a day. Some studies have suggested selumetinib may intended to be a be helpful for patients who are at high risk of the cancer returning after definitive statement surgery. More studies are now aiming to show how it may work best in on the safety, combination with radioactive iodine therapy, which is currently used. efficacy or effectiveness of the If selumetinib is licensed for use in the UK, it could be a new treatment health technology option for patients with differentiated thyroid cancer that may reduce covered and should symptoms of the disease and increase survival. not be used for commercial purposes or NIHR HSRIC ID: 9968 commissioning 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

• Differentiated thyroid cancer: newly diagnosed with high risk of primary treatment failure – first line; in combination with radioactive iodine therapy.

TECHNOLOGY

DESCRIPTION

Selumetinib (selumetinib hydrogen sulfate; ARRY-889; ARRY-142886; AZD-142886; AZD- 6244; NSC-748727) is an oral, potent selective mitogen activated protein kinase (MEK) inhibitor, which has been shown to be effective against MEK-dependent tumours. Over activation of this pathway is known to be associated with the loss of expression of the sodium iodide symporter in thyroid cells, rendering them resistant to radioiodine therapya. By inhibiting the MEK signalling pathway, selumetinib can prevent extracellular signal related kinase activation, disrupt downstream signal transduction, and inhibit cancer cell proliferation, and survival. In the phase III clinical trial, selumetinib is administered orally at 75mg twice daily for approximately 5 weeks, in combination with radioactive iodine therapy1.

Selumetinib does not currently a have Marketing Authorisation in the EU for any indication. It is in phase III clinical trials for non-small cell lung cancer (combination therapy, second or subsequent line). Selumetinib is also in phase II development for the treatment of biliary cancer (combination therapy), colorectal cancer (combination therapy) and iodine refractory thyroid cancer (monotherapy).

INNOVATION and/or ADVANTAGES

If licensed, selumetinib will offer an additional first line oral treatment option for patients with high-risk differentiated thyroid cancer.

DEVELOPER

AstraZeneca UK Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

The thyroid gland is located at the base of the throat near the trachea and consists of a right and left lobe connected by a thin piece of tissue called the isthmus2. Thyroid cancer arises from cells in the tissues of the thyroid gland2. There are four different types of thyroid cancer3, but most common thyroid cancers are differentiated cancers which develop from thyroid follicular cells4. These include papillary, follicular and Hurthle cell carcinomas4,10, and account for about 90% of all thyroid cancer4.

a Expert personal communication.

2 Horizon Scanning Research & Intelligence Centre

Papillary carcinoma is slow growing but often spreads to lymph nodes in the neck4. Follicular carcinoma is more common in countries where there is iodine deficiency in the diet. It does not often spread to local or regional lymph nodes, but may metastasise to other parts of the body, such as the bone or lungs4.

The most common symptom of thyroid cancer is a painless lump in the neck5. In advanced disease, other symptoms of local invasion may include unexplained hoarseness, a sore throat, difficulty swallowing, and pain5.

A number of risk factors can increase the likelihood of developing thyroid cancer. Approximately 20% of thyroid cancers occur in people who have had benign thyroid disease, such as adenomas, goitre, and thyroiditis3. Additionally, a small number of thyroid cancers are caused by radiation exposure3. It is also thought that people who are overweight may have a higher risk of developing thyroid cancer3.

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: Head and Neck (Adult). B16/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a. • NHS England. 2013/14 NHS Standard Contract for Specialised Endocrinology Services (Adults). A03/S/a. • NHS England. 2013/ 14 NHS Standard Contract for Brachytherapy and Molecular Radiotherapy (All Ages). B01/S/b.

CLINICAL NEED and BURDEN OF DISEASE

Thyroid cancer is the 20th most common cancer in the UK (2012)6. It is the most common malignant endocrine tumour, but represents less than 1% of all malignancies13. Worldwide, incidence of thyroid cancer is increasing; in England, the incidence of thyroid cancer has increased by 150% since 19757. Expert opinion advises that though the global incidence of thyroid cancer is increasing, this has not been accompanied by an increase in thyroid cancer mortalityb. This suggests that increasing incidence could be due to low risk thyroid disease diagnosed incidentally on imaging investigations for other conditions; low risk disease would not be considered for this particular interventionb.

Thyroid cancer is approximately two-and-a-half times more common in women than in men. In 2013 there were 2,791 new cases of thyroid cancer reported in England, 745 males and 2,046 females8. In the same year, the incidence of thyroid cancer in England was estimated to be 7.7 per 100,000 population in women, and 3.1 per 100,000 population in men8. In 2014-15, there were 6,038 hospital admissions due to thyroid cancer (ICD-10 C73) in England, accounting for 6,354 finished consultant episodes and 15,000 bed days9.

Differentiated thyroid cancers are generally associated with a favourable prognosis; however, recurrence occurs in 10-15% of patients after surgery10. Distant metastases are

b Expert personal communication.

3 Horizon Scanning Research & Intelligence Centre

detected in less than 10% of patients at diagnosis, but are the main cause of mortality10. In 2014, there were 332 deaths in England where thyroid cancer was recorded as the underlying cause11.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE interventional procedure guidance. Minimally invasive video-assisted parathyroidectomy (IPG501). August 2014. • NICE interventional procedure guidance. Minimally invasive video-assisted thyroidectomy (IPG499). August 2014. • NICE interventional procedure guidance. Thoracoscopic excision of mediastinal parathyroid tumours (IPG247). December 2007.

Other Guidance

• The American Thyroid Association. Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. 201512. • British Thyroid Association. Guidelines for the management of thyroid cancer. 201413. • European Society for Medical Oncology. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 201214.

CURRENT TREATMENT OPTIONS

The most common treatment for localised, differentiated thyroid cancer is partial or total thyroidectomy15. This may be followed by radioactive iodine treatment15. Radiotherapy can be utilised post-thyroidectomy but this is uncommonc. Effective therapies for patients with differentiated thyroid carcinoma who do not respond to radioiodine treatment are lacking, with conventional chemotherapy, such as doxorubicin and/or cisplatin16, proving relatively ineffective10. Sorafenib and lenvatinib are both licensed in the EU to treat metastatic differentiated thyroid carcinomas that are refractory to radioactive iodine treatment17,18.

EFFICACY and SAFETY

Trial ASTRA, NCT01843062, D1532C00065, EudraCT 2013-000423-14; selumetinib vs placebo, both in combination with radioactive iodine therapy; phase III. Sponsor AstraZeneca. Status Ongoing. Source of Trials registry1. information Location EU (not UK), USA and Brazil. Design Randomised, placebo-controlled. Participants n=304 (planned); aged ≥18 years; differentiated thyroid cancer; tumour >4cm or gross extra-thyroid extension, or one lymph node >1cm, or five or more lymph nodes of any size; previous thyroidectomy; no metastatic disease; no anaplastic or medullary thyroid cancer; no Hurthle cell carcinoma; no presence of anti-thyroglobulin antibodies; no previous treatment with any radiation.

c Expert personal communication.

4 Horizon Scanning Research & Intelligence Centre

Schedule Randomised to selumetinib 75mg oral three times daily; or placebo oral three times daily; both in combination with radioactive iodine therapy, 100mCi (131I) oral administered 30 days after randomisation. Follow-up Active treatment for 5 weeks, follow-up 18 months. Primary Complete remission rate. outcome/s Secondary Clinical remission rate, frequency of adverse events, pharmacokinetics. outcome/s Expected Study completion date reported at March 2019. reporting date

ESTIMATED COST and IMPACT

COST

The cost of selumetinib 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: the company claim that if selumetinib reduces the rate of relapse in patients with thyroid cancer, the number of patients requiring services for metastatic disease will also be reduced.

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

 Other.  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs: the company  Reduced drug treatment costs: expert opinion states that there is likely to be an increase in advises that current licensed treatments for initial drug costs, although reduced numbers differentiated thyroid cancer are associated of patients with relapsed disease may mean a with considerable expense and ongoing reduction in other costs for further treatments toxicity as they are taken daily until disease and services. progression. This may be for a period of several years. The proposed treatment period length for selumetinib is 4-5 weeks, which could reduce treatment cost and toxicityd.

 Other increase in costs.  Other reduction in costs.

 Other:  None identified

d Expert personal communication.

5 Horizon Scanning Research & Intelligence Centre

Other Issues

 Clinical uncertainty or other research question  None identified identified.

REFERENCES

1 ClinicalTrials.gov. Study comparing complete remission after treatment with selumetinib/placebo in patient with differentiated thyroid cancer (ASTRA). www.clinicaltrials.gov/ct2/show/NCT01843062 Accessed 7 December 2015. 2 National Cancer Institute. Thyroid cancer treatment. www.cancer.gov/types/thyroid/patient/thyroid-treatment-pdq Accessed 7 December 2015. 3 MacMillan. Thyroid Cancer. www.macmillan.org.uk/Cancerinformation/Cancertypes/Thyroid/Thyroidcancer.aspx Accessed 8 December 2015. 4 American Cancer Society. What is thyroid cancer? http://www.cancer.org/cancer/thyroidcancer/detailedguide/thyroid-cancer-what-is-thyroid-cancer Accessed 8 December 2015. 5 Cancer Research UK. Thyroid cancer symptoms. www.cancerresearchuk.org/about- cancer/type/thyroid-cancer/about/thyroid-cancer-symptoms Accessed 7 December 2015. 6 Cancer Research UK. Thyroid cancer statistics. www.cancerresearchuk.org/health- professional/cancer-statistics/statistics-by-cancer-type/thyroid-cancer#heading-Zero Accessed 7 December 2015. 7 Finlayson A, Barnes I, Sayeed S et al. Incidence of thyroid cancer in England by ethnic group, 2001-2007. British Journal of Cancer 2014;110(5):1322-1327. 8 Health & Social Care Information Centre. Cancer registration statistics, England, 2013. www.hscic.gov.uk/hes 9 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk/hes 10 Leboulleux S, Bastholt L, Krause T et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. The Lancet Oncology;13(9):897-905. 11 Office for National Statistics. Mortality statistics: deaths registered in England and Wales, series DR, 2014. www.ons.gov.uk 12 Alexander E, Bible K, Doherty G et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid online 2015; doi:10.1089/thy.2015.0020 13 Perros P, Colley S, Boelaert K et al. Guidelines for the management of thyroid cancer. Clinical Endocrinology 2014;81(1):1-122. 14 Pacini F, Castagna M, Brilli L et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23(7):110-119. 15 National Institute for Health and Care Excellence. Minimally invasive video-assisted thyroidectomy. Interventional procedure guidance (499). London: NICE; August 2014. 16 Cancer Research UK. About chemotherapy for thyroid cancer. www.cancerresearchuk.org/about- cancer/type/thyroid-cancer/treatment/chemotherapy/about-chemotherapy-for-thyroid-cancer#how Accessed 8 December 2015. 17 electronic Medicines Compendium (eMC). Nexavar 200mg film-coated tablets. www.medicines.org.uk/emc/medicine/18520 Accessed 8 December 2015. 18 electronic Medicines Compendium (eMC). Lenvima 4mg and 10mg hard capsules. www.medicines.org.uk/emc/medicine/30412 Accessed 14 December 2015.

6