Cabozantinib for medullary thyroid cancer February 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 National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research
Cabozantinib for medullary thyroid cancer Target group Medullary thyroid cancer: unresectable, locally advanced or metastatic first or later line. Background Thyroid cancer is classified histologically according to cell type, and represents the most common type of malignant endocrine tumour 1. Papillary and follicular thyroid cancers, which account for the vast majority of thyroid tumours, arise from follicular thyroid cells and are commonly referred to together as differentiated thyroid cancer (DTC) 1. Other remaining cancers of the thyroid include medullary and anaplastic thyroid cancer, and thyroid lymphoma 2. Medullary thyroid cancer (MTC) originates from the calcitonin secreting parafollicular C-cells of the thyroid gland and is thought to account for 5-10% of all thyroid cancers 3. The majority of MTC cases are sporadic, however approximately 25% are hereditary owing to a mutation in the RET (REarranged during Transfection) proto-oncogene 4. Hereditary MTC can be seen in isolation (familial MTC) or as part of the multiple endocrine neoplasia syndrome type 2 (MEN 2A or 2B) 4. Technology description Cabozantinib (XL-184) is an inhibitor of multiple receptor tyrosine kinases, including MET, vascular endothelial growth factor receptor 2 (VEGFR2) and RET. MET plays a key role in cellular proliferation, migration and angiogenesis, and is mutationally activated in various tumour types. Overexpression of VEGF has been observed in a number of different cancers, while RET mutations play a key role in tumourigenesis, both in sporadic and familial MTC 5. In preclinical studies, treatment with cabozantinib demonstrated a decrease in tumour invasiveness and decreased metastasis compared with agents targeting VEGF signalling without MET inhibition 5. In the phase III clinical trial, cabozantinib was administered orally at 175mg once daily 6. Cabozantinib is also in phase III clinical trials for metastatic prostate cancer and in phase II trials for breast cancer, ovarian cancer, melanoma, hepatocellular carcinoma, non-small cell lung cancer and other advanced solid tumours. Innovation and/or advantages If licensed for this indication, cabozantinib may provide a new treatment option for this patient group, who currently have limited effective therapeutic options. Developer Exelixis. 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 cancer service guidance. Service guidance on improving outcomes in head and neck cancer. 2004 7. 2
American Thyroid Association. Medullary thyroid cancer: management guidelines of the American Thyroid Association. 2009 8. American Thyroid Association. Revised American Thyroid Association Management 9 guidelines for patients with thyroid nodules and differentiated thyroid cancer. 2009. British Thyroid Association, Royal College of Physicians. Guidelines for the management of thyroid cancer in adults. Second edition. 2007 3. Clinical need and burden of disease Although thyroid cancer represents the most common type of malignant endocrine tumour 1, it accounts for less than 1% of all cancers in the UK 10. In England and Wales, 1,918 people were diagnosed with thyroid cancer in 2008, an incidence of approximately 3 per 100,000 population 10. MTC is a relatively rare form of thyroid cancer accounting for only 5-10% of all cases 3, however it is also one of the more aggressive forms with a worse survival rate compared to DTC 4. Expert opinion suggests aggressive forms of MTC often occur in younger patients with an estimated 50 cases per year in the UK a. The overall survival of patients with MTC has been reported as 75% (ranging from 61% to 88%) at 10 years follow-up 4, however the prognosis of patients with MTC varies considerably. In 2010-2011, there were 4,936 admissions for thyroid cancer in England, resulting in 15,040 bed days and 5,175 finished consultant episodes 11. In England and Wales, 300 deaths due to thyroid cancer were registered in 2010 12 (ICD10 C73). Existing comparators and treatments The only curative treatment for MTC is currently surgical resection. This usually consists of total or near-total thyroidectomy with lymph node dissection 4. The clinical utility of adjuvant radiotherapy is unclear and opposing findings have been reported 4. Adjuvant external beam radiotherapy has not been shown to improve survival 13, however it may improve the relapse-free rate if there is residual or extensive nodal disease 14. Radiotherapy may also be utilised in cases of unresectable MTC to control local symptoms 3. Treatment with cytotoxic chemotherapy has generally proved ineffective 3 and is rarely helpful b. As a result, no standard chemotherapy regimen has been developed 4. Radiolabelled somatostatin and/or 131 I-metaiodobenzylguanidine ( 131 I-MIBG) may be useful in a small number of patients with symptomatic, metastatic MTC 3,4. Efficacy and safety Trial EXAM, NCT00704730, XL184-301; cabozantinib vs placebo; phase III. Sponsor Exelixis. Status Ongoing. Source of Trial registry 15 and manufacturer 6. information Location EU (inc UK), USA, Canada and other countries. Design Randomised, placebo-controlled. Participants and schedule n=315; adults 18 years; unresectable, locally advanced or metastatic progressive MTC; no prior treatment within 4 weeks of randomisation. Randomised to cabozantinib 175mg once daily or placebo. Follow-up Continuous treatment until disease progression; follow-up for survival ongoing. Primary Progression-free survival (PFS). outcome Secondary outcome Overall survival; objective response rate; duration of response; safety and tolerability; pharmacokinetics and pharmacodynamics. a Expert personal communication 3
Key results Adverse effects (AEs) Interim results: PFS for cabozantinib vs placebo respectively, 11.2mths vs 4.0mths, hazard ratio 0.28 (95% CI: 0.19-0.40), p<0.0001. AEs were reportedly consistent with previously published information: in a phase I trial a total of 77 patients (90%) reported at least one treatment-related AE. Of these, 43% were grade 1 or 2 AEs, with the most frequent being diarrhoea, fatigue, decreased appetite, nausea, palmar-plantar erythrodysesthesia, rash, increased aspartate transaminase levels, vomiting and mucosal inflammation. Treatmentrelated hypertension of grade 3 occurred in two patients (2%) and of grade 1-2 in 12 patients (14%). One grade 4 treatment related event occurred (pulmonary embolism) and there were no treatment-related grade 5 events 5. Estimated cost and cost impact The cost of cabozantinib is not yet known. Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Reduction in associated morbidity or Improved quality of life for patients and/or carers Quicker, earlier or more accurate diagnosis or identification of disease None identified Services Increased use: Patients currently Service organisation Staff requirements managed by palliative services would remain longer in the specialised oncology sector. 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 treatment option. Savings: Other: Other issues Clinical uncertainty or other research question identified: Expert opinion suggests tyrosine kinases are not well tolerated in many patients and subsequent adverse effects may prove a barrier to widespread use. None identified References 1 Brown RL, De Souza JA, Cohen EE. Thyroid cancer: Burden of illness and management of disease. Journal of Cancer 2011;2:193-199. 2 Wilson PC, Millar BM and Brierley JD. The management of advanced thyroid cancer. Clinical Oncology. 2004;16:561-568. 3 British Thyroid Association and Royal College of Physicians. Guidelines for the management of thyroid cancer: second edition. London: Royal College of Physicians; 2007. 4 Kebebew E, Clark OH. Medullary thyroid cancer. Current Treatment Options in Oncology 2000;1:359-367. 5 Kurzrock R, Sherman SI, Ball DW et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. Journal of Clinical Oncology 2011;29(19):2660-2666. 6 Exelixis. News Release. Phase 3 results in medullary thyroid cancer. http://www.exelixis.com/cabozantinib/clinical-trial-information/medullary-thyroid-cancer Accessed 1 December 2011. 7 National Institute for Health and Clinical Excellence. Service guidance on improving outcomes in head and neck cancers. Cancer service guidance CSGHN. London: NICE; November 2004. 4
8 Kloos RT, Eng C, Evans DB et al. Medullary thyroid cancer: Management guidelines of the American Thyroid Association. Thyroid 2009;19(6):565-612. 9 Cooper DS, Doherty GM, Haugen BR et al. Revised American Thyroid Association Management guidelines for patients with thyroid nodules and differentiated cancer. Thyroid 2009;19:1167-1214. 10 Cancer Research UK. Thyroid cancer statistics UK. http://info.cancerresearchuk.org/cancerstats/types/thyroid/?script=true Accessed 1 December 2011. 11 NHS Hospital episode statistics. NHS England 2010-2011 HES data. 2011. 12 Office for National Statistics. Mortality statistics deaths registered in 2010, series DR 2010 www.statistics.gov.uk 13 Fife KM, Bower M, Harmer C. Medullary thyroid cancer: the role of radiotherapy in local control. European Journal of Surgical Oncology 1996;22:588-591. 14 Wilson PC, Millar BM, Brierley JD. The management of advanced thyroid cancer. Clincal Oncology 2004;16:561-568. 15 ClinicalTrials.gov. Efficacy of XL184 (Cabozantinib) in advanced medullary thyroid cancer (EXAM) http://clinicaltrials.gov/ct2/show/nct00704730?term=cabozantinib+and+thyroid&rank=1 Accessed 1 December 2011. The National Institute for Health Research National 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 National 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 5