Lenvatinib and sorafenib for differentiated thyroid cancer after radioactive iodine: a systematic review and economic evaluation

Article history

The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 16/51/20. The protocol was agreed in January 2017. The assessment report began editorial review in August 2017 and was accepted for publication in November 2017. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

none

Copyright statement

© Queen’s Printer and Controller of HMSO 2020. This work was produced by Fleeman et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

2020 Queen’s Printer and Controller of HMSO

Thyroid cancer: overview

Thyroid cancer is a rare cancer, representing only 1% of all malignancies in England and Wales. 1 It is caused by the growth of abnormal cells in the thyroid gland. This is a small gland at the base of the neck that secretes three hormones: triiodothyronine (T₃), thyroxine (T₄) and calcitonin. T₃ and T₄ control the rate of metabolism in the body, and calcitonin works with the parathyroid hormone to control the amount of calcium in the blood. 2 Thyroid cancer is usually asymptomatic and is often discovered incidentally via imaging studies [e.g. sonograms, computerised tomography (CT) scans and magnetic resonance imaging (MRI)] that are carried out for another reason, or when patients present with a large palpable nodule in the neck. 3 The actual diagnosis of thyroid cancer is usually made using ultrasonography and biopsy (typically, a fine-needle aspiration). 4

The incidence of thyroid cancer is increasing worldwide. 4–10 In the UK, between the period 2003–5 and the period 2012–14, thyroid cancer incidence rates increased by 74% (Figure 1). 1 In 2014, there were 3404 patients diagnosed with thyroid cancer in the UK, 2941 in England and 123 in Wales. 1 The reasons for the increase in incidence are unknown, but are thought to be, at least in part, attributable to improved diagnostic and detection techniques. 11

FIGURE 1.

Average number of new cases per year per 100,000 people in the UK. Based on a graphic created by Cancer Research UK. 1

Based on a graphic created by Cancer Research UK

The incidence of thyroid cancer is 2.5 times greater in women than in men. 1 The reasons for this disparity are unclear. 12 Thyroid cancer incidence is strongly related to age, with the highest incidence rates being in older males, and the highest incidence rates among females being in younger and middle-aged women (Figure 2).

FIGURE 2.

Age-specific incidence rates per 100,000 people in the UK. Based on a graphic created by Cancer Research UK. 1

Based on a graphic created by Cancer Research UK

In the UK, thyroid cancer accounts for < 1% of male cancer deaths and < 1% of female cancer deaths. 13 The mortality rate in the UK is reported to be < 1 death per 100,000 people. 13 In 2014, there were 376 thyroid cancer deaths in the UK, 154 (41%) in males and 222 (59%) in females, giving a male-to-female ratio of around 7 : 10. In England and Wales, there were 331 thyroid cancer deaths: 137 in males and 194 in females. 13

Although the incidence of thyroid cancer in the UK increased between the period 2003–5 and the period 2012–14, overall mortality rates remained stable during this time (Figure 3);13 however, between 1970 and 2014, thyroid cancer mortality rates decreased by 46% in the UK, the decrease being more marked in females (54%) than in males (24%). 13 Mortality rates for thyroid cancer are projected to rise in the future: in the UK, it is expected that between 2014 and 2035 mortality will increase by 7%; however, the overall rate is expected to remain relatively low at 1 death per 100,000 people. 13

FIGURE 3.

European age-standardised thyroid cancer mortality rates in the UK: 1971–2014. Based on a graphic created by Cancer Research UK. 13

Based on a graphic created by Cancer Research UK

Differentiated thyroid cancer

The most common form of thyroid cancer is differentiated thyroid cancer (DTC); DTC is reported to account for approximately 94% of thyroid carcinomas. 14,15 Less common types of thyroid cancer include medullary carcinoma and anaplastic carcinoma; these have been reported to account for approximately 4% and approximately 2% of all thyroid carcinomas, respectively. 15

Differentiated thyroid cancer is a specific type of thyroid cancer made up of different subtypes including papillary carcinoma (PTC), follicular carcinoma (FTC) and Hürthle cell carcinoma. PTC is the most common type of DTC, accounting for approximately 83%15 to 86%16 of all cases; FTC accounts for approximately 10%16 to 13%,15 and Hürthle cell carcinoma accounts for approximately 3%15 to 4%. 16 Hürthle cell carcinomas are usually grouped with FTCs because they present and behave similarly. 17

The median age for all patients with DTC is reported to be 45 years;18 however, estimates of the median age at onset for the subtypes of DTC have been reported to vary:

• Papillary carcinoma often affects people aged < 40 years,17 but it is also reported that the median age of patients with PTC is 45 years. 19

• The peak age for the onset of FTC has been stated to be between 40 and 60 years,20 but, again, the median age has been reported to be approximately 45 years. 21

• The median age of patients with Hürthle cell carcinoma has been reported to be 55 years. 21

In general, the prognosis for patients with DTC is relatively good. The overall 10-year survival rate for middle-aged adults is reported to be 80–90%. 4 It has also been reported that > 85% of patients with DTC have a ‘normal’ life expectancy;22 however, the prognosis generally gets worse with increasing age at the time of diagnosis, particularly for patients aged ≥ 45 years. 4 In addition, young children (aged < 10 years) are at higher risk of recurrence than older children. 4 Prognosis may also be affected by DTC subtype (histology). An analysis of US National Cancer Database data on 41,375 patients with DTC who were treated between 1985 and 199515 has shown that the 10-year relative survival for patients with PTC is 93%, whereas for patients with FTC it is 85%, and for patients with Hürthle cell carcinoma it is 76%.

The size and spread of the tumour affect prognosis. Studies cited by the British Thyroid Association (BTA)4 are reported to show that the risk of recurrence and mortality correlates with the size of the primary tumour. Extrathyroidal invasion, lymph node metastases and distant metastases are also reported to be important prognostic factors. 4

First-line treatment options for patients with differentiated thyroid cancer

There are currently no National Institute for Health and Care Excellence (NICE) guidelines and no NICE guidance for treating patients with DTC or any other type of thyroid cancer. Other clinical guidelines do present some recommendations. In chronological order from date of publication, relevant clinical guidelines include the European Society for Medical Oncology (ESMO) guidelines (2012),23 BTA guidelines (2014),4 American Thyroid Association guidelines (2015)24 and National Comprehensive Cancer Network (NCCN) guidelines (2017). 25

Owing to the indolent course of the disease, many patients with DTC, even if they have metastatic disease, do not require therapy for several years after diagnosis. 26 Treatments for DTC depend on factors including age, extent of disease, and histology, but usually involve surgery to remove all or part of the thyroid gland (thyroidectomy) followed by lifelong thyroxine for thyroid-stimulating hormone (TSH) suppression from the low–normal to fully suppressed range dependent on risk factors. 4,23–25

Treatment options for patients with differentiated thyroid cancer that has progressed following surgery

Following initial surgery, it is estimated that between 5% and 20% of patients with DTC develop local or regional recurrences (approximately two-thirds of these involve cervical lymph nodes27) and between 10% and 15% of patients with DTC develop distant metastases. 4,24 The most common sites for metastases are reported to be the lungs (50%), bones (25%), lungs and bones (20%) or other (5%). 24 It has been noted that the presence of bone metastases has been associated with a worse prognosis than metastases in other sites. 23

The sites that DTC is most likely to spread to vary by histology. For patients aged > 40 years, it has been reported that 10% of patients with PTC, 25% of patients with FTC and 35% of patients with Hürthle cell carcinoma develop distant metastases. 28,29 PTC tends to spread to lymph nodes in the neck, whereas FTC usually spreads to the bones or lungs. 17 Hürthle cell carcinoma is more likely than FTC to spread to lymph nodes in the neck. 30

A radioactive iodine uptake test is commonly used to determine whether or not DTC has spread. The test involves a patient being given a liquid or capsule containing radioactive iodine (iodine-123) to swallow. Two separate uptake measurements are then commonly obtained at different time points within a 24-hour period. The patient is then scanned to see how much of this radioactive iodine has been absorbed by the thyroid (radioactive uptake). Positive results (evidence of iodine-123 uptake) denote the presence of disease, whereas negative results (no radioactive uptake) denote the absence of disease.

It is recommended in clinical guidelines4,23–25 that patients with DTC and evidence of radioactive iodine uptake should undergo treatment with radioactive iodine (also known as radioactive iodine ablation) to treat residual, recurrent or metastatic disease. Patients are typically tested 1–2 months after surgery. Radioactive iodine treatment has been used for > 60 years. It is administered in hospital (during an inpatient stay) and can be given to patients on more than one occasion, as necessary. 4

Like the radioactive iodine uptake test used to diagnose DTC, radioactive iodine treatment involves swallowing radioactive iodine in either liquid or capsule form; however, the radioactive iodine is a different form (iodine-131) to that used for scans (iodine-123): the purpose of radioactive iodine treatment is to destroy cancerous cells. Thus, patients with iodine-131 uptake are responsive to treatment, which can be confirmed by imaging studies.

Approximately 33% of patients with advanced disease can be cured and many others achieve long-term disease stabilisation. 31 From published French registry data,32 the 10-year survival rate for patients with distant metastases who successfully responded to treatment with radioactive iodine is 92%. 32

Radioactive iodine-refractory differentiated thyroid cancer

Although for many patients radioactive iodine is an effective treatment, some patients become resistant to the treatment (decreased or no radioactive iodine uptake) or are unable to safely tolerate additional doses. These patients are considered to have radioactive iodine-refractory DTC (RR-DTC) and are the focus of this multiple technology appraisal (MTA).

Although clinical criteria and algorithms have been developed and reported in clinical guidelines,4,23–25 there is no agreed precise definition of RR-DTC;33 however, a review of the literature published in February 201731 highlights key features that can be considered in defining RR-DTC:

• Metastatic disease that does not take up radioactive iodine at the time of the first radioactive iodine treatment.

• Ability to take up radioactive iodine has been lost after previous evidence of uptake of radioactive iodine.

• Radioactive iodine uptake is retained in some lesions but not in others.

• Metastatic disease that progresses despite substantial uptake of radioactive iodine.

• Absence of complete response to treatment after > 600 mCi of cumulative activity of radioactive iodine.

• Evidence of high uptake of fludeoxyglucose (FDG) ¹⁸F on positron emission tomography or CT scan; however, importantly, the authors of this review31 state that this reason alone should not be used to abandon radioactive iodine treatment.

Before deciding whether or not a patient’s disease can be described as being RR-DTC, it is important to determine that decreased radioactive iodine uptake is not due to iodine contamination or insufficient TSH. 34

Radioactive iodine-refractory DTC is a life-threatening form of thyroid cancer with a tendency to progress and metastasise. 14 From published French registry data,32 the 10-year survival rate and median overall survival (OS) for patients with distant metastases who failed to respond to treatment (no iodine-131 uptake) was 10% and 3 years, respectively. For those who appear to respond to radioactive iodine treatment (iodine-131 uptake) but who did not then attain negative imaging studies, the 10-year survival and median OS was 29% and 6 years, respectively. A separate analysis of patients with lung and/or bone metastases35 found that 10-year survival and median OS for those who did not have a complete response to treatment with radioactive iodine was 14% and 5 years, respectively. Data from Canada5 have suggested that the median OS for patients with RR-DTC may be between 2.5 and 3.5 years.

The proportion of patients whose disease becomes refractory to treatment with radioactive iodine is relatively small, and so RR-DTC is described as an ultra-orphan condition. 7,8 Estimates of the proportion of patients who become refractory vary but commonly lie within the range of 5–15%. 7,8,14,16,32,35–37

As with early-stage DTC, many patients with RR-DTC are initially asymptomatic. As highlighted in a literature review published by Schmidt et al.,31 even patients with distant metastases may have a disease that does not progress for many years; however, as noted by Thyroid Cancer Canada,5 the cancer continues to progress with no obvious symptoms.

For patients with rapidly progressing disease, which is characterised by symptomatic disease, the symptoms of RR-DTC can be severe, profoundly debilitating and result in patients becoming increasingly dependent on carers. 8 Clinical advice to the Assessment Group (AG) is that the percentage of patients with RR-DTC with rapidly progressing disease is likely to be approximately 25% to 30%. As a result of their symptoms, patients with clinically significant progressive RR-DTC may suffer a poor quality of life and the psychological impact of the disease can also be substantial, resulting in low mood and fatigue. 38 It has also been stated that patients with RR-DTC often experience multiple complications. 39

Treatment options for patients with radioactive iodine-refractory differentiated thyroid cancer

Radioactive iodine-refractory DTC is typically asymptomatic, but symptoms start to occur as the disease progresses. Symptoms associated with lymph nodes of the neck include difficulty swallowing and/or breathing, pain or sensitivity in the front of the neck or throat, hoarseness or other voice changes, and swelling of the lymph nodes in the neck. 4 Symptoms associated with lung metastases also include swallowing and breathing difficulties. 26 Pain often presents as the principal symptom of metastatic bone involvement. 29,40 Fractures and spinal cord compression are also associated with bone metastases.

Because many treatments, particularly systemic treatments, can have severe side effects and impact significantly on health-related quality of life (HRQoL), clinical advice to the AG is that best supportive care (BSC) tends to be the preferred treatment option, at least until symptoms occur. BSC typically entails TSH suppression therapy and imaging every 3 to 12 months. Palliative radiotherapy and symptom relief are also offered when necessary.

Patients experiencing RR-DTC symptoms and/or patients with rapidly progressing disease are those in need of systemic treatment,31 as reflected in clinical guidelines. 4,23–25 The aim of systemic treatment for patients with rapidly progressing and/or symptomatic RR-DTC is to gain local disease control in the neck and manage systemic disease. 41 Another important objective of treatment is to prolong survival;27 however, treatment options for patients with RR-DTC are limited. Within the ESMO guidelines published in 2012,23 it is stated that chemotherapy should not be given to patients with RR-DTC as it is associated with significant toxicity with no proven evidence of effectiveness. The authors of these guidelines stated that surgical resection and external beam radiotherapy represented the only therapeutic options and they strongly encouraged enrolment of patients in experimental trials with targeted therapy. Similarly, the authors of the guidelines published by the BTA in 20144 only recommended chemotherapy for patients with rapidly progressive, symptomatic RR-DTC who have good performance status (PS), and only when access to targeted therapies in clinical trials is unavailable or when targeted therapies have proved unsuccessful. The authors of the more recent US guidelines published by the American Thyroid Association24 and NCCN25 recommend that patients with RR-DTC should usually avoid treatment with chemotherapy. Clinical advice received by the AG is that chemotherapy is rarely used to treat RR-DTC in UK NHS practice.

Targeted therapies were not widely available and were only the subject of clinical trials between 2012 and 2014, when the ESMO guidelines23 and the BTA guidelines4 were published. The authors of the BTA guidelines4 considered the most promising targeted therapies at that time to be lenvatinib and sorafenib. 4 By 2017, the authors of the NCCN guidelines25 recommended lenvatinib or sorafenib as the treatment of choice for patients with progressive and/or symptomatic disease; lenvatinib is stated to be the ‘preferred’ option based on a response rate of 65% for lenvatinib, compared with 12% for sorafenib, although these agents have not been directly compared. However, the authors state that the decision should be based on the individual patient, taking into account the likelihood of response and comorbidities. 25 In cases in which lenvatinib or sorafenib are not available or not appropriate, drugs not regulated by the US Food and Drug Administration (FDA) but used in the context of clinical trials are also recommended by the authors of the NCCN guidelines. 25

Description of technology under assessment

The two interventions under consideration in this MTA are lenvatinib (Lenvima), manufactured by Eisai Ltd, and sorafenib (Nexavar), manufactured by Bayer HealthCare. Both are a type of tyrosine kinase inhibitor (TKI) known as a multikinase inhibitor (MKI).

A brief comparison of the key features of the two interventions is given in Table 1. The AG notes that lenvatinib and sorafenib appear to have slightly different mechanisms of action. 42 Both drugs have been approved for treating RR-DTC in the USA43,44 and Europe,49,50 with sorafenib being the first of the two agents to be approved in both jurisdictions. In the USA and Europe, the marketing indications for both lenvatinib and sorafenib are for identical patient populations. Approval in the USA and Europe was based largely on evidence from two Phase III randomised controlled trials (RCTs): SELECT,51 in which lenvatinib was compared with placebo, and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer),52 in which sorafenib was compared with placebo.

Approval for use in NHS Scotland was granted to sorafenib in June 201548 and to lenvatinib in September 2016. 38 Both approvals are for the treatment of patients with progressive, locally advanced or metastatic RR-DTC. In NHS Scotland, the use of both lenvatinib and sorafenib is contingent on the continuing availability of Patient Access Scheme (PAS) prices that have been assessed by the PAS Assessment Group.

Sorafenib has been available in England, since July 2016, via the Cancer Drugs Fund (CDF). It is currently funded for all patients with RR-DTC for whom the treating specialist has established that treatment with sorafenib may be beneficial. According to Bayer HealthCare, based on its analysis of notification data from July 2013 to June 2016, sorafenib has become the standard of care for patients for whom systemic treatment is appropriate. 7 Lenvatinib is not currently available to patients treated in the English or Welsh NHS.

Eisai Ltd8 has estimated the incidence of patients in England and Wales with RR-DTC who are potentially eligible for treatment with lenvatinib or sorafenib to be approximately 280 each year. Bayer HealthCare7 has estimated the incidence to be approximately 225 patients per year. The AG notes that the estimates given by the companies differ in how they are calculated. The estimates provided by the companies are reflective of the population defined by the agreed final scope of this appraisal; however, neither estimate appears to account for the fact that lenvatinib and sorafenib are likely to only be preferred for patients with symptomatic and/or rapidly progressing disease. Clinical advice to the AG is that there are no generally agreed definitions of ‘symptomatic’ or ‘rapidly progressive disease’ and that, in clinical practice, definition of a patient’s disease status depends on individual patient characteristics. Therefore, it is difficult to further segment the population.

Decision problem addressed by the Assessment Group

The decision problem for this appraisal, as described in the final scope issued by NICE,53 is summarised in Table 2.

The overall aims and objectives of the assessment

The aim of this research was to assess the clinical effectiveness and cost-effectiveness of lenvatinib versus sorafenib, within their respective EU marketing authorisations,45,46 for the treatment of patients with RR-DTC. The research objectives are given below:

• To carry out systematic reviews to compare the clinical effectiveness and cost-effectiveness of –

  • treatment with lenvatinib with treatment with sorafenib for RR-DTC

  • treatment with lenvatinib with BSC for RR-DTC

  • treatment with sorafenib with BSC for RR-DTC.

• To develop an economic model to compare the cost-effectiveness of –

  • treatment with lenvatinib with treatment with sorafenib for RR-DTC

  • treatment with lenvatinib with BSC for RR-DTC

  • treatment with sorafenib with BSC for RR-DTC.

Search strategy

The AG identified clinical studies and systematic reviews by searching EMBASE, MEDLINE, PubMed and The Cochrane Library from 1999 onwards. All databases were searched on 10 January 2017. Based on the fact that the FDA approved sorafenib for its first indication in 2005, and lenvatinib in 2015, the AG considered that this date span would allow all relevant clinical evidence to be identified. Searches were restricted to publications in English language. The AG did not use any other search filters. The search strategies used by the AG are provided in Appendix 1. In addition to the electronic database searches, information on studies in progress was sought (on 16 May 2017) by searching the ClinicalTrials.gov website, the International Clinical Trials Registry Platform and the European Union Clinical Trials Register. The references in the systematic reviews included in the AG’s review of systematic reviews, and those listed in the submissions from professional stakeholders that were submitted to NICE, as part of the NICE MTA process, were cross-checked to identify any relevant studies not retrieved from the electronic database searches. Literature search results were uploaded to and managed using EndNote X7.4 [Clarivate Analytics (formerly Thomson Reuters), Philadelphia, PA, USA] software.

Study selection

The eligibility criteria listed in Table 3 were used to identify studies for inclusion in the AG’s literature review.

Two reviewers (JH and RH) independently screened all titles and abstracts that were identified in the initial searches (screening stage 1). Based on the titles and abstracts, full-text papers that appeared to be relevant were obtained and assessed for inclusion by the same two reviewers in accordance with the AG’s eligibility criteria (screening stage 2). When necessary, discrepancies were resolved by consultation with a third reviewer (NF). At both stages of screening, studies that did not meet the inclusion criteria were excluded, and, at screening stage 2, the reasons for excluding studies were noted.

The eligibility criteria in Table 3 differ slightly from those specified in the AG’s systematic review protocol. 55 The AG, responding to a suggestion from NICE in relation to the final protocol,55 agreed to include evidence from prospective observational studies that had been submitted to the European Medicines Agency (EMA); however, as only reviewing studies included in the EMA submissions26,27 would have introduced selection bias, the AG included all prospective observational studies of patients with RR-DTC identified by its searches.

Data extraction and quality assessment strategy

Data relating to RCT study characteristics and outcomes were extracted by one reviewer (NF) and independently checked for accuracy by a second reviewer (YD). Data relating to study characteristics and outcomes of systematic reviews and observational studies were extracted by one reviewer (JH or NF) and independently checked for accuracy by a second reviewer (JG). In all cases, a consensus was reached. Study data reported in multiple publications were extracted and reported as a single study. Data were extracted into tables in Microsoft Word (Microsoft Corporation, Redmond, WA, USA).

As specified in the AG’s systematic review protocol,55 the quality of included RCTs and systematic reviews was assessed according to the criteria set out in the Centre for Review and Dissemination’s guidance56 for undertaking reviews in health care. The quality of the included RCTs was assessed by one reviewer (YD) and independently checked for agreement by a second reviewer (NF). In all cases, a consensus was reached. The quality of the included systematic reviews was assessed by one reviewer (JG) and independently checked for agreement by a second reviewer (YD). When necessary, discrepancies were resolved by consultation with a third reviewer (MR).

Methods of analysis/synthesis

The AG’s data extraction and quality assessment results are presented in structured tables and as a narrative summary. Data from RCTs are considered to provide primary clinical effectiveness evidence, with data from systematic reviews and observational studies considered to provide supporting evidence.

As the available evidence did not include two or more RCTs comparing the same intervention, the AG was not able to conduct a meta-analysis of RCT data.

The AG assessed the feasibility of conducting an indirect comparison of effectiveness data (including a comparison to assess effectiveness according to previous treatment with TKIs) by evaluating the clinical and methodological heterogeneity of the included RCTs. Heterogeneity was assessed by comparing (1) trial characteristics, (2) participant characteristics, (3) outcome data and (4) study quality.

Quantity and quality of research available

Included studies

The process of study selection is shown in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram in Figure 4. The electronic searches yielded 2358 papers, and six additional references5–8,57,58 were identified through other sources. In total, the AG included 93 papers5–8,33,51,52,57–142 reporting on 24 separate studies and reviews: two unique RCTs,51,52 13 unique systematic reviews5–8,33,57,61,93,97,104,127,138,141 and nine unique prospective observational studies. 59,77,78,81,88,101,103,126,135

FIGURE 4.

The PRISMA flow diagram: studies included in AG’s systematic review. Reproduced with permission from Fleeman et al. 54 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original text.

Reproduced with permission from Fleeman et al. 54 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original text.

Evidence from randomised controlled trials

Only two RCTs were identified as relevant for inclusion in the AG’s systematic review: SELECT and DECISION. Except when stated otherwise, all information about these two trials has been extracted from the two key trial publications. 51,52

Subgroup analyses from randomised controlled trials

Only subgroup analyses considered by the AG to be of direct relevance to the decision problem have been reported in the remainder of this report. The AG considered the following subgroup analyses to be relevant (with rationale given):

• patients previously treated and not previously treated with TKIs (prespecified subgroup in the NICE scope53 and AG decision problem)

• patients with and without symptomatic disease at baseline (as highlighted in Chapter 1, Treatment options for patients with radioactive iodine-refractory differentiated thyroid cancer, systemic treatment is recommended for patients who have symptomatic disease)

• analyses of subgroups that were prespecified in the trials and in which there appeared to be differences in baseline characteristics within or across trials (as differences in baseline characteristics may influence results).

As previously highlighted, the AG concluded that the assumption of PH does not hold in any of the analyses that it was able to check other than unadjusted OS in DECISION. This means that the majority of the survival HRs generated using data from SELECT and DECISION and, consequently, statements about the statistical significance of results should be interpreted with caution.

Extended open-label phases of SELECT and DECISION

In the extended open-label phase of SELECT, the starting daily dose of lenvatinib was originally 24 mg. This was later modified to 20 mg and then reverted to 24 mg. It is important to note that this phase of the trial only included 115 patients who crossed over from the placebo arm to lenvatinib and therefore does not present evidence from a randomised or controlled patient population. Furthermore, only placebo-treated patients who had confirmed disease progression (independent blinded review) during the randomisation phase and who met protocol-specified eligibility criteria were treated with lenvatinib. Consequently, it is noted in the EPAR27 for lenvatinib that these patients had very advanced disease, because they had experienced two sequential, confirmed disease progressions: the first before randomisation at the time of study entry and the second during treatment with the study drug in the randomisation phase.

The extended open-label phase of DECISION differed to that of SELECT in that as well as including patients who crossed over from the placebo arm to receive sorafenib, it also included patients who remained on sorafenib. In total, 150 patients in the placebo arm crossed over to receive sorafenib at progression and of these, data from 137 patients were evaluable for efficacy. In addition, 55 patients randomised to the sorafenib arm continued on sorafenib treatment in the open-label extension phase, of which 46 patients were evaluable for efficacy. It is reported by Schlumberger et al. 122 and Paschke et al. 114 that patients evaluable for efficacy had poorer risk features at enrolment compared with patients who were not evaluable. Like the extended open-label phase of SELECT, evidence from this patient population does not comprise evidence from a randomised or controlled patient population.

Findings from the extended open-label phase of SELECT for only ‘. . . the more mature dataset of patients who started treatment at the 24mg lenvatinib dose’ were reported in a conference abstract118 describing the first data cut-off point (November 2013). Findings reported at the second data cut-off point (June 2014) were presented for patients who started treatment at the 20-mg dose of lenvatinib and for patients who started the 24-mg dose of lenvatinib in the EPAR for lenvatinib. 27 In the EPAR,27 it is reported that patient characteristics, previous treatments, geographical allocation, on-study placebo exposure, lenvatinib exposure in the extended open-label phase and median follow-up times vary considerably for these two dose regimens. Thus, patients receiving the different dose regimens are considered by the EMA to represent different populations of patients.

In addition to conference abstracts,114,122 the findings from the extended open-label phase of DECISION have been reported in the EPAR46 for sorafenib. Safety data for the extended open-label phase of DECISION are reported in the submission from Bayer HealthCare. 7

The efficacy and safety findings from the open-label phases of both trials are summarised in Appendix 7, Tables 56 and 57. OS data have not been reported. With the exception of median PFS for patients receiving sorafenib for a second time, which was 6.7 months, the efficacy findings for PFS from the extended phase of SELECT and DECISION were similar to the findings reported in the randomised phase of the trials. The incidence of AEs for patients treated with lenvatinib and sorafenib in the open-label phases of the two trials tended to be slightly lower than reported during the double-blind phase.

In addition, Kappeler et al. 94 and Fassnacht et al. 83 have reported exploratory analyses of tumour growth rate in the randomised double-blind and extended open-label phases of DECISION. The authors found that the tumour growth rate (mean changes per month of sum of target lesion diameters) from baseline to nadir was –3.9% then +2.6% from nadir to progression for patients treated with sorafenib in the randomised phase; for those continuing with additional sorafenib in the open-label phase, from second baseline to progression the tumour growth rate was +1.7%. For patients randomised to the placebo arm, the tumour growth rate was +5.0% for all placebo patients and it was +6.1% for placebo patients subsequent to crossing over to receive sorafenib. Patients in the placebo arm who crossed over to sorafenib in the open-label phase then experienced a tumour growth rate pattern similar to that of patients who started on sorafenib in the randomised phase: –4.4% from second baseline to nadir and then +1.8% from nadir to progression.

Associations between tumour response, progression-free survival, overall survival, safety and health-related quality of life

Gianoukakis et al. 86 examined the association between ORR and PFS for patients treated with lenvatinib in SELECT. The analysis is based on the third data cut-off point (August 2015) using investigator-assessed ORR [60.2% (the proportion of patients who achieved an objective tumour response)] and investigator-assessed mean PFS (19.4 months). The authors found that the median PFS in patients who received lenvatinib and who demonstrated a tumour response was 33.1 months (95% CI 27.8 months to not estimable). In lenvatinib-treated patients who did not show tumour response, the median PFS was 7.9 months (95% CI 5.8 to 10.7 months). Robinson et al. 117 reported that an exploratory multivariate analysis found that percentage change in tumour size at the first assessment was a marginally statistically significant positive predictor for PFS (p = 0.06).

Using data from the first data cut-off point of SELECT, Newbold et al. 108 analysed PFS by patients who had responded to treatment with lenvatinib at the first tumour assessment (median time to response 1.9 months) and by those who responded later (median time to response 3.8 months). The authors found that there was no difference in PFS between patients who achieved objective response at the time of first tumour assessment compared with thereafter.

Haddad et al. 91 found from a multivariate analysis (first data cut-off point) that in SELECT, all-grade diarrhoea was statistically significantly associated with OS (median OS for lenvatinib-treated patients with diarrhoea was not reached and median OS for lenvatinib-treated patients without diarrhoea was 17.1 months). Choi et al. 79 reported that the results of a post hoc analysis showed that lenvatinib-treated patients with hypertension had higher median PFS than those without hypertension (18.8 vs. 12.9 months; p = 0.009). Haddad et al. 91 also reported results from multivariate analyses of associations between five other AEs (proteinuria, diarrhoea, fatigue/asthenia/malaise, rash and hand–foot syndrome) and PFS in SELECT. No statistically significant associations between any of the AEs and PFS were found.

Using data from DECISION, Kappeler et al. 95 carried out an exploratory analysis to explore the association between tumour growth rate and PFS and OS. It is reported that the data cut-off points used for PFS and OS were the first data cut-off point (August 2012) and third data cut-off point (July 2015), respectively. Values of early tumour growth rate were split into quartiles [by median times derived from Kaplan–Meier (K–M) curves and from modelling with a Weibull distribution] separately by treatment arm. Better prognosis for PFS and OS with sorafenib was associated with the second and third tumour growth rate quartiles.

No other analyses have been conducted for patients treated with either lenvatinib or sorafenib in SELECT or DECISION examining the relationships between any of the efficacy or safety outcomes and HRQoL. As reported earlier (see Health-related quality-of-life findings), it has been speculated that AEs did affect HRQoL based on data from FACT-G and EQ-5D questionnaires, but no formal analyses have been conducted in an attempt to correlate the findings.

Indirect comparison feasibility assessment

In the absence of direct clinical evidence comparing treatment with lenvatinib versus sorafenib, the AG considered whether or not it was appropriate to carry out an indirect comparison to obtain estimates of the relative efficacy and safety of these two treatments.

The first step was to determine whether or not SELECT and DECISION shared a common comparator. The comparator arm of both trials was placebo. From the limited information on the placebos reported by Eisai Ltd,8 Bayer HealthCare7 and in the published papers,51,52 the AG considered that the comparator arms were likely to be similar and that a network could be constructed (Figure 5).

FIGURE 5.

Indirect comparison network.

The second step was to check the comparability of the participant and trial characteristics between the two trials. As described in Trial characteristics and Participant characteristics, the AG has noted that there are several trial design and participant differences, both within and between SELECT and DECISION. These differences raised concerns about whether or not data from these trials should be included in the same network of evidence.

The final step undertaken by the AG was to examine the PFS K–M data from the placebo arms of SELECT and DECISION to determine the extent to which the risk profiles of the populations in these arms of the two trials were comparable. The AG concluded that the risks were not sufficiently comparable and that these two trials should, therefore, not be included in the same network of evidence.

The Assessment Group’s detailed commentary on progression-free survival Kaplan–Meier data from the placebo arms

An indirect comparison implicitly assumes that the randomised patients are drawn from similar populations with reference to their risk profile for the time-to-event outcomes (PFS and OS). Because PFS is the primary outcome specified in both clinical trials, it is important that the equivalence of the placebo arms of the two trials can be confirmed by comparison of PFS outcomes: any significant discrepancy in progression risk would invalidate an indirect comparison between lenvatinib and sorafenib.

Figure 6 compares the K–M PFS trial results for the placebo arms of the two trials. After similar trends over the first 2 months, the curves separate markedly for more than a year before crossing over in the long term. Visual examination is sufficient to establish that these data are not amenable to either a simple HR adjustment or a time ratio adjustment.

FIGURE 6.

Comparison of PFS in the placebo arms of DECISION and SELECT. Reproduced with permission from Fleeman et al. 54 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original text.

Reproduced with permission from Fleeman et al. 54 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original text.

Further exploration of these data trends through a plot of cumulative hazards in the two trial arms at common time points reveals a clear divergence from a simple linear (PH) relationship (Figure 7). The trial data indicate a higher initial risk of disease progression in SELECT in the first 10 months, followed by a sharp reversal in which the risk in the SELECT placebo arm reduces by > 50%.

FIGURE 7.

Comparison of PFS hazard trends in the placebo arms of DECISION and SELECT.

The AG considers that the placebo arms of SELECT and DECISION exhibit unexpectedly inconsistent patterns of temporal change that are not compatible with the assumption that these are similar patient groups. Consequently, patients enrolled in the two trials cannot be considered to be derived from a common population and, therefore, conducting an indirect comparison to obtain estimates of relative efficacy for lenvatinib and sorafenib is not appropriate.

Systematic review evidence

The AG included 13 systematic reviews5–8,33,57,61,93,97,104,127,138,141 in its review; these reviews included the evidence submissions reporting systematic reviews and indirect comparisons for this MTA from Eisai Ltd8 and Bayer HealthCare,7 and also the evidence reported in a paper by Tremblay et al. 57 Although Tremblay et al. 57 did not report the conduct of a systematic review, this paper was included as it did report results from an indirect comparison and a matching-adjusted indirect comparison (MAIC) using data from SELECT and DECISION.

A summary of the characteristics of the included systematic reviews is presented in Appendix 5, Table 49. Most of the evidence was derived from observational studies of treatment with sorafenib. However, four of the reviews,7,8,57,97 including the submissions from Eisai Ltd8 and Bayer HealthCare,7 included evidence from SELECT and DECISION and results from indirect comparisons, including MAICs.

The AG’s assessment of the quality of the included reviews is presented in Appendix 5, Table 50. Overall, the AG considered that the quality of nine5–8,61,97,104,127,138 of the identified systematic reviews was good. However, only 45–8 of the 13 reviews included a quality assessment of the included primary studies. Four33,57,93,141 of the reviews were considered to be of poorer quality than the rest. Of these, only one33 reported the use of an adequate search strategy. In addition, methods of cross-checking during either the study selection process or the data extraction process were not reported by the authors of three reviews. 33,57,93 No quality assessment of the primary studies was reported in any of these four reviews. 33,57,93,141

The conclusions reached by the authors of the systematic reviews are presented in Appendix 5, Table 51. The earliest of the reviews was carried out by Anderson et al. 61 and was published in 2013. The authors concluded that certain treatments, notably TKIs, showed promise in Phase II trials. Gruber and Colevas33 concluded that the most likely outcome of treatment with a TKI was stable disease. McFarland and Misiukiewicz104 concluded that sorafenib slowed the progression of disease in the majority of cases. For treating thyroid cancer, Ye et al. 141 reported that the clinical effects of sorafenib and lenvatinib outweigh the toxicities [relative risk (RR) 1.27, 95% CI 1.05 to 1.53] and deaths (RR 15.24, 95% CI 6.99 to 33.21). Ye et al. 141 concluded that lenvatinib and sorafenib were more useful for thyroid cancer than for RR-DTC, based on the results of the subgroup analyses that were conducted. However, the AG considers that all of the studies that included patients with DTC also included patients with RR-DTC and so the validity of this subgroup analysis and the conclusions reached based on these subgroup analyses are questionable.

Jean et al. 93 found AEs reported for sorafenib for treating RR-DTC to be higher than for AEs reported for treating renal cell carcinoma (RCC) or hepatocellular carcinoma (HCC). In two reviews127,138 ORR data and AE data were pooled for sorafenib from seven observational studies59,78,88,101,126,147,148 (five prospective and two retrospective). In the review by Shen et al. ,127 all of the studies59,78,88,101,126,147,148 included patients with RR-DTC, whereas the review by Thomas et al. 138 included five prospective observational studies of RR-DTC,59,88,101,126,147 a retrospective study of RR-DTC149 and a Phase II study150 of patients with medullary thyroid cancer. Although the incidences of hand–foot syndrome (≥ 73%), diarrhoea (≥ 68%) and weight loss (≥ 50%) included in both meta-analyses were broadly similar to the incidence of the same AEs in DECISION, it was noticeable that the incidences of rash (≥ 66%) and fatigue (≥ 60%) were higher than reported in DECISION. Similarly, the pooled ORR (20.9% to 22%) from the two reviews127,138 was higher than the ORR reported in DECISION. The pooled median PFS (17.9 months) from the review by Thomas et al. 138 was also higher than median PFS reported in DECISION, but the pooled analysis for PFS also included patients with medullary thyroid cancer. The key results from these three reviews93,127,138 are summarised in Appendix 5, Table 52.

In addition, Shen et al. 127 noted that rare but severe AEs were observed mainly due to intracranial haemorrhage, cardiac arrest, angiooedema, small cell lung cancer, carcinoma of the tongue, and grade 5 event of sudden death. Because of the limited data, the authors did not pool these high-grade AEs. Thomas et al. 138 also reported that bleeding at any site occurred in 13.6% of patients, 3.8% of patients reported acute myocardial infarctions and 2.2% experienced congestive heart failure. Severe hypocalcaemia (grade ≥ 3) occurred in 2.5% of patients and 8.7% of patients developed cutaneous squamous cell carcinoma. However, it should be cautioned that in the meta-analyses conducted by Shen et al. 127 and Thomas et al. ,138 the authors did not investigate the heterogeneity of the studies included in the meta-analyses.

For RR-DTC, all of the indirect comparison results (including results from MAICs7,57) showed that lenvatinib was statistically significantly superior to sorafenib in terms of PFS but not OS. 6–8,57,97 Kawalec et al. 97 also reported lenvatinib to result in statistically significantly fewer cases of alopecia but statistically significantly more cases of hypertension and treatment-related SAEs, when compared with sorafenib. Bayer HealthCare7 reported sorafenib to result in fewer grade ≥ 3 AEs, SAEs and withdrawals owing to AEs when compared with lenvatinib. However, caveats about the generalisability of the results of the indirect comparisons have been raised,6 and Kawalec et al. 97 stated that indirect comparison results should be interpreted with caution because of differences in trial characteristics. Furthermore, during the current appraisal, Bayer HealthCare confirmed that it considered that the data from its indirect treatment comparison (ITCs)7 did not enable a robust comparison of sorafenib and lenvatinib given important differences between SELECT and DECISION. 151 Of the indirect comparisons conducted, only the indirect comparison by Kawalec et al. 97 was not sponsored by Eisai Ltd or Bayer HealthCare. A summary of the findings from the indirect comparisons is presented in Appendix 5, Tables 53–55.

Evidence from prospective observational studies

The AG included nine prospective observational studies in its review. 59,77,78,81,88,101,103,126,135 Five of these studies59,78,88,101,126 were included in the meta-analyses conducted by Shen et al. 127 and by Thomas et al. 138 Seven of the studies were included in the EPARs26,27 for lenvatinib77,135 and sorafenib. 59,78,88,101,126 The study and participant characteristics and efficacy and safety findings are summarised in Appendix 8, Tables 58–68.

All studies included patients whose disease was described as being radioactive iodine-refractory59,77,78,101,126,135 or resistant to radioactive iodine,81,88 or who may have received multiple treatments of radioactive iodine. 103 Two studies77,135 investigated the efficacy and safety of lenvatinib, six studies59,78,88,101,103,126 assessed the efficacy and safety of sorafenib and one study81 considered the efficacy of sorafenib. Some patients included in four of the studies59,88,101,135 had anaplastic or medullary carcinoma. Safety data from these four studies59,88,101,135 are, therefore, not reported for RR-DTC only. However, all nine studies59,77,78,81,88,101,103,126,135 reported efficacy findings for patients with RR-DTC only and all efficacy data reported in this section related to patients with RR-DTC only.

The E7080-G000-201 study (hereafter referred to as Study 20177) of lenvatinib was conducted in the UK, France, Italy, Poland, the USA and Australia. The E7080-J081-208 study of lenvatinib (hereafter referred to as Study 208135) was conducted in Japan. Studies of sorafenib were carried out in the UK,59 the Netherlands,126 Italy,103 Greece,81 the USA101 and China. 78 The earliest study was conducted between 2004 and 2005,101 and the most recent study was conducted between 2012 and 2015. 135 The length of study follow-up varied from a minimum of 3 months78 to a median of 51.6 months. 27

The number of patients included in the studies varied from 978 to 58. 77 In total, 109 patients were treated with lenvatinib, of whom 83 had RR-DTC; 213 patients were treated with sorafenib, of whom 186 had RR-DTC. In most studies, the majority of patients with RR-DTC had a histology of PTC,59,77,78,88,101,126 the exception being the study by Marotta et al. 103 in which the ratio of patients with FTC to patients with PTC was 2 : 1. The average age of participants ranged from 55 years59 to 64 years. 101 Four studies59,77,88,101 included a majority of males and three studies81,103,126 had a majority of females. Two studies78,135 did not report information on sex. The authors of only two studies77,101 reported information on race and these included a majority of white participants. Only two studies that reported ECOG status included patients with an ECOG PS of ≥ 2 (6.9%77 and 35.3%103). The same two studies were the only studies to explicitly state that patients could have received a prior TKI (11.8%103 to 29.3%77). There was scant and inconsistent reporting of the sites of metastases.

Median OS was reported in five studies. 77,88,101,126,135 Median OS ranged from 31.8 months135 to 32.3 months77 for lenvatinib and from 23 months101 to 34.5 months126 for sorafenib. Median PFS was reported in six studies77,88,101,103,126,135 and ranged from 12.6 months77 to 25.8 months135 for lenvatinib and from 12 months103 to 22.1 months for sorafenib88 (this last finding was reported in a subsequent conference abstract137). Chen et al. 78 (sorafenib) reported mean PFS (9.7 months). The ORRs ranged from 50.0%77 to 68.0%135 for patients treated with lenvatinib, and from 15% (histology of PTC)101 to 38.3%88 for those treated with sorafenib (this latter finding was reported in a subsequent conference abstract137). Median time to response and median duration of response were only reported in two studies. 77,126 For lenvatinib,77 median time to response was 3.6 months and, for sorafenib,126 all responses were reported to have happened within 6 months. The median duration of response was 12.7 months for lenvatinib77 and 29.6 months for sorafenib. 126

Key AEs are summarised in Appendix 8, Tables 61–66. Two studies88,101 (sorafenib) only reported treatment-related AEs. Two of the sorafenib studies,78,81 presented only as abstracts, reported very little information about AEs.

Incidences of the same types of AEs varied across the studies: for lenvatinib, hypertension and proteinuria were very commonly reported; for sorafenib, hand–foot syndrome, rash and alopecia were common; and diarrhoea and fatigue were common with both drugs. Data on SAEs were available only from Study 20177 (lenvatinib). Information on fatal AEs were reported only in two studies77,135 of lenvatinib and in one study101 of sorafenib. For patients treated with lenvatinib, 48% reported a SAE77 and up to 8%135 died from an AE. Only one death from AEs has been reported in one of the studies of sorafenib;101 it is unclear if the lack of reporting of fatal AEs in the other sorafenib studies59,78,81,88,103,126 means that there were no deaths from AEs in these studies. None of the deaths from AEs in any of the three studies77,101,135 reporting fatal AEs were described as being treatment related.

Ongoing studies and studies for which there are no results

The AG identified four ongoing studies,152–155 as summarised in Appendix 9 (see Table 69). None of the study results has been published or reported as a conference abstract. Only the two studies of lenvatinib154,155 are RCTs: E7080-G000-211 (Study 211)154 is a Phase II postauthorisation study that includes a randomised controlled phase, comparing two different starting doses of lenvatinib (24 vs. 18 mg) with placebo; E7080-C086-308 (Study 308)155 is a Phase III RCT being conducted in China comparing lenvatinib at its licensed dose of 24 mg with placebo. Eisai Ltd sponsors both of these trials. The other two studies are prospective observational Phase II studies of sorafenib:152,153 a pilot study sponsored by the Royal Marsden NHS Foundation Trust152 and a postauthorisation study sponsored by Bayer HealthCare. 153

In addition, although not strictly meeting the inclusion criteria for the current MTA, the AG is aware of an ongoing global prospective non-interventional study [Radioactive Iodine reFractory asymptomatic patients (RIFTOS), NCT02303444]156 of asymptomatic patients with RR-DTC treated with any type of MKI. The primary objective is to compare the time to symptomatic progression from study entry. Bayer HealthCare sponsors this study. The planned enrolment is approximately 700 patients and the expected study end date is 1 July 2020.

Discussion of clinical effectiveness: interpretation of results

The AG’s assessment of lenvatinib and sorafenib for the treatment of patients with RR-DTC focused on evidence from two RCTs: SELECT (lenvatinib vs. placebo) and DECISION (sorafenib vs. placebo). Supporting evidence was derived from 13 systematic reviews5–8,33,57,61,93,97,104,127,138,141 (including two systematic reviews described in the submissions from Eisai Ltd8 and Bayer HealthCare7) and nine prospective observational studies. 59,77,78,81,88,101,103,126,135

Search strategy

The AG identified cost-effectiveness studies by searching EMBASE, MEDLINE, the NHS Economic Evaluation Database via The Cochrane Library and EconLit from 1999 onwards. The starting date for all of the searches was 1999 and all databases were searched on 10 January 2017. Based on the fact that the FDA approved sorafenib for its first indication in 2005, and lenvatinib in 2015, the AG considered that this date span would allow all relevant economic evidence to be identified. The reference lists of included publications, in addition to the NICE, SMC and CADTH websites, were hand-searched. The results of the searches were entered into an EndNote X7.4 library and de-duplicated.

Study selection and inclusion criteria

Publications were selected for inclusion in the review based on their relevance to the decision problem and the specific economic criteria presented in Table 12. In addition to costs, quality-adjusted life-years (QALYs), cost–benefit and cost-effectiveness outcomes, such as cost per PFS year, were also extracted from relevant publications.

Two reviewers (RH and NF) independently screened the titles and abstracts of all publications identified by the searches. The same two reviewers then independently retrieved and assessed (for inclusion) the full texts of the publications that had been identified as being potentially relevant to the review. Disagreements about inclusion in the review were resolved through discussion and, in all cases, a consensus was reached; it was, therefore, not necessary to consult a third reviewer during the screening and selection process.

Quantity of evidence

The searches for economic evidence identified 19 citations in total: 14 were obtained from the database searches and five were identified from other sources. Once duplicates were removed, 18 publications remained and, after assessment of the titles and abstracts, 10 publications5,38,48,158–164 were retrieved and a detailed assessment of their eligibility was undertaken.

Nine of these 10 publications were included in the review. The AG included four publications158–160,163 that clearly met the inclusion criteria. The AG considered that the economic evidence for lenvatinib and sorafenib that had been submitted to the SMC38,48 and CADTH5,162 was also relevant to this review and so these four records,5,38,48,162 one for each drug’s individual submission to each regulatory agency, were included in the review. One further relevant publication161 was identified during the citation search of the included publications; this publication became available online only after the AG’s database searches had been completed.

One publication164 was a budget impact analysis and was, therefore, excluded from the review.

A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram showing the process of study selection is shown in Figure 8.

FIGURE 8.

The PRISMA flow diagram: the AG economic literature review.

A summary of the characteristics of the nine included publications5,38,48,158–163 is presented in Table 13.

Quality of the included evidence

The quality of the included evidence was assessed using the NICE reference case checklist169 and the Drummond checklist. 170 Summary tables of the AG’s quality assessments are presented in Appendices 11 (see Table 72) and 12 (see Table 73). Full details of the completed checklists are presented in Appendices 13 (see Tables 74–81) and 14 (see Tables 82–89). The publications by Huang et al. 158,159 have been evaluated together as the same economic model was used to generate results for both publications.

Only the Wilson et al. 161 publication was available as a full-text paper published in a peer-reviewed journal. Three of the included publications158,159,163 were available only as abstracts, and one publication160 was available as a poster. The submissions to the regulatory bodies in Scotland38,48 and Canada5,162 were available only as summary reports. As a result, only limited information was available from most of the included publications and this hindered the quality assessment of some of the methodologies described in the publications.

The authors of all of the included publications produced incremental cost-effectiveness estimates enabling a single metric [an incremental cost-effectiveness ratio (ICER) per QALY gained] to be used for comparative purposes. All of the publications included a discussion of the certainty associated with study results; however, full details of the sensitivity analyses and parameter values were not always available in the text.

Generally, the text describing the assumptions and data sources used to generate resource use, costs and HRQoL estimates within the economic models was not clear. In addition, it was unclear whether or not the costs and benefits described in the publications were discounted appropriately. Results from analyses of the cost-effectiveness of all the relevant comparators (lenvatinib, sorafenib and BSC) were available from only four of the reviewed publications. 158–161

None of the publications considered the decision problem from the perspective of the NHS in England. However, as the Scottish NHS provides a sufficiently similar environment to the NHS in England, the AG considered that, for the purposes of this appraisal, the results from the SMC submissions38,48 are broadly generalisable to patients in England. The characteristics of the health-care systems, in terms of the way treatments are procured and used in the USA,158,159,161 Canada5,162 and Turkey,163 make the results from analyses based on these perspectives less useful when considering treatment options for patients in the NHS in England. However, including these studies5,158,159,161–163 in this review allows a broad range of cost-effectiveness estimates to be considered and provides some indication of the effect of varying assumptions, such as the model time frame and estimates of HRQoL.

The Assessment Group’s review of economic evidence: summary and conclusions

The published economic evidence163 shows that the ICER of £23,859 per QALY gained for the comparison of sorafenib with BSC (after conversion from Turkish lira) is within the willingness-to-pay threshold that is considered to reflect a cost-effective use of NHS resources. However, without further details of the economic model inputs, in particular the resource use and costs, the relevance of this finding to the NHS setting is unclear.

In the US setting, when compared with placebo, both treatment with lenvatinib and treatment with sorafenib appear to provide additional health benefits while either saving resources158 or yielding ICERs per QALY gained of < £50,000 after conversion from US$ (£31,566 per QALY gained161 for lenvatinib versus placebo and £49,484 per QALY gained161 for sorafenib vs. placebo). When treatment with lenvatinib is compared with sorafenib in the US setting, lenvatinib offers a health benefit over sorafenib but at an increased cost. Cost-effectiveness results ranged from £19,522 per QALY gained161 (lenvatinib vs. sorafenib) to £96,671 per QALY gained160 (lenvatinib vs. sorafenib), at current UK prices. Again, it is unclear whether or not these results are relevant to the NHS setting.

In 2015, sorafenib became the standard of care for patients in Scotland with locally advanced or metastatic RR-DTC, provided that the company supplied the drug to the NHS at the Scottish PAS price agreed by the company with NHS Scotland. 48 The SMC sorafenib report48 states that sorafenib generated more benefit than BSC but at an increased cost. The ICER for this comparison was £32,083 per QALY gained. In 2016, an appraisal of treatment with lenvatinib38 versus sorafenib was submitted to the SMC; lenvatinib was considered by the SMC to be both an orphan drug and an end-of-life treatment. For the comparison of treatment with lenvatinib with treatment with sorafenib, based on survival outcome results generated using indirect comparison methods, and using the Scottish PAS price for lenvatinib, the ICER per QALY gained was estimated to be £49,525 and lenvatinib was accepted for use in NHS Scotland.

The AG notes that any discount to the list prices of the drugs agreed with the NHS in Scotland does not equate to an equivalent agreement with the NHS in England. All PAS prices are confidential and thus the applicability of the results presented within the Scottish submissions to the appraisal of lenvatinib and sorafenib for use in the NHS in England is unclear as it is not known whether or not the discounts agreed with the NHS in Scotland are the same as those agreed with the NHS in England.

In 2015, sorafenib was appraised by CADTH5 and, after reanalyses suggested by the Economic Guidance Panel, estimates of the most plausible ICERs for the cost-effectiveness of treatment with sorafenib versus BSC ranged from £108,974 to £118,913 per QALY gained (after conversion from CA$). Lenvatinib was considered for use by the Canadian health-care system in 2016. Estimates of the cost-effectiveness of treatment with lenvatinib versus both BSC and sorafenib were generated but only the comparisons with BSC are reported in the CADTH report. 162 After the Economic Guidance Panel’s suggested amendments were carried out, the best estimate for the comparison of treatment with lenvatinib versus BSC was £101,293 per QALY gained. Both lenvatinib and sorafenib have been recommended for use in Canada. The relevance of these results to patients in the NHS is unknown.

What is lacking from the current evidence base are any cost-effectiveness analyses of direct relevance to the NHS in England. The SMC submissions38,48 provide an insight into the costs and consequences associated with treatment with lenvatinib, sorafenib and BSC, and these are likely to be similar for patients treated in England. However, the PAS prices agreed with the NHS in Scotland are confidential and this prevents the reported cost-effectiveness estimates being directly applicable to the NHS in England.

Head-to-head comparisons of the effectiveness of treatment with lenvatinib with the effectiveness of treatment with sorafenib depend on results from indirect comparisons, whether conducted in a formal statistical framework5,38,48,160,162 or with adjustments made to the placebo arms of the Phase III trials,161 which provide estimates based on the pooling of the comparator arms within the SELECT and DECISION Phase III trials. The AG considers that, because of the issues discussed in Chapter 4, Indirect comparison feasibility assessment, it is not appropriate to employ indirect comparisons of the effectiveness of lenvatinib and the effectiveness of sorafenib using data from SELECT and DECISION.

Summary of the companies’ systematic reviews of economic evidence

Both of the companies carried out systematic reviews to identify published cost-effectiveness studies that included lenvatinib and/or sorafenib. Both companies concluded that there are no cost-effectiveness studies conducted in the UK from the perspective of the NHS that were relevant to decision-making in England. Therefore, both companies produced their own de novo economic evaluations.

Summary of the key features of the companies’ economic models

This section includes summary details of the key features of the economic models submitted to NICE, from Eisai Ltd and Bayer HealthCare, as part of the MTA process. All of the company data presented in this section are drawn from the company submissions7,8 and models.

The Assessment Group’s independent cost-effectiveness assessment

Model design

In common with the two companies, the AG has used a standard partitioned survival model structure, applied to the patient population specified in the final scope issued by NICE,53 to consider the cost-effectiveness of treatment with lenvatinib and sorafenib compared with BSC (as represented by data from the placebo arms of SELECT and DECISION).

Two particular differences should be noted:

1. The AG has not included a separate health state for patients who respond to treatment. On clinical advice, the AG considers that there is little merit in this addition to the standard three-state structure (in which patients begin in the progression-free health state and, following assessed disease progression, transfer to the postprogression state in which they receive only BSC prior to death). For responding patients, who are mostly symptom-free, response alone is unlikely to have a measurable effect on patient-perceived quality of life/utility and has no effect on resource use.

2. The AG has designed a model that allows each intervention (lenvatinib and sorafenib) to be represented in its natural time metric: 30-day cycles for lenvatinib and 28-day cycles for sorafenib. This involved creating two parallel models using the same assumptions and model parameters, but each with its own placebo arm calibrated from its respective clinical trial data. Although not ideal, the AG has provided an illustrative structural sensitivity analysis (Figure 9) based on applying data from the counterfactual placebo arm of both trials to illustrate the extent of uncertainty involved in comparisons between the active treatments with the currently available clinical evidence. The reason for this unusual approach is to demonstrate non-equivalence of the placebo arms of the two clinical trials, which renders indirect comparison of the two treatments via a common comparator invalid (as discussed in Chapter 4, Indirect comparison feasibility assessment, and illustrated graphically in Figure 9).

FIGURE 9.

Model structure featuring two simple trial-based comparisons, with additional cross-trial comparisons as a structural sensitivity analysis to illustrate the uncertainty associated with choice of comparator.

Resource use estimation, the sources for unit costs and selection of health-related utility values used in the AG’s model are presented in this section. Standard discount rates of 3.5% per annum are used for discounting both costs and benefits (measured as QALYs), but not for life-years (survival). The AG model is structured with a maximum time horizon of 40 years.

Effectiveness data

Modelling long-term outcomes from trial data

Both companies have followed a conventional approach to the general problem of identifying an appropriate method by which to extrapolate time-limited follow-up trial data for PFS, OS and time to treatment discontinuation. This involves attempting to fit a range of prespecified statistical functions to the available evidence, and selecting one that appears to be optimal according to particular ‘measures of fit’ (principally the Akaike information criterion and the Bayesian information criterion).

This paradigm is wholly dependent on the limited data available and the restricted armoury of ‘standard’ models. In particular, it fails to take into account a wider evidence base specifically related to the natural history of the disease, and the influence of particular characteristics of both the recruited patient group and of the trial design.

The AG has investigated long-term survival trends in patients diagnosed with Stage 3 or 4 (locally advanced or metastatic) thyroid cancer in the USA and recorded on the Surveillance Epidemiology and End Results (SEER) database. 177 A total of 32,818 patients (male and female) followed for 15 years yielded a persistent trend from 18 months after diagnosis. Figure 10 demonstrates the very close match between these data and a simple linear model, indicating that the risk of death remained unchanged throughout this period, which is indicative of a simple exponential survival process.

FIGURE 10.

Cumulative hazard data from follow-up of patients diagnosed with stage III/IV thyroid cancer for 15 years.

This evidence is sufficiently compelling to give the AG confidence to employ exponential extrapolation as the default method of modelling incomplete trial data in this appraisal. The nature of clinical trials (selecting patients who have suffered a recent disease progression, and administering a novel treatment that takes time to reach full effectiveness) means that the initial period post randomisation will give rise to temporary distortions to the underlying disease process. However, thereafter, it is likely that the natural history of the condition will be re-established, so that a long-term exponential function will reappear. The mean time since diagnosis of patients randomised in DECISION was 7.24 years, suggesting that the trial cohort lies in the middle of the follow-up range shown in Figure 10. The AG is therefore confident that outcome data extrapolation should be focused on fitting exponential models to estimate lifetime survival expectation.

Data issues

Following the initial stakeholders’ meeting for this appraisal (17 February 2017), the AG submitted identical requests to the two companies, asking for a set of detailed analyses of the latest data available from the two clinical trials, based on common analytical methods to allow comparative analyses to be carried out by the AG; thus, minimising the risk of methodological bias. Eisai Ltd provided the requested data relating to SELECT as an appendix to the submission. 8 Unfortunately, Bayer HealthCare chose not to address the AG’s request. As a consequence, the AG was unable to conduct some comparative analyses based on common assumptions, and the potential for bias and uncertainty in the data available to the AG remains.

The two clinical trials that provide the effectiveness evidence for this appraisal share common features, which result in interpretive complexity and uncertainty. In particular, in both trials patients were permitted to cross over from the placebo control to the active treatment (lenvatinib or sorafenib) following disease progression. As a consequence, randomisation was broken in both trials and some outcome variables may not be mutually compatible, even after attempts to adjust for crossover effects.

Both companies assume that, in addition to the active treatments, a third comparator (BSC) may be represented by the placebo arms of the two trials. Moreover, it is implicitly assumed that the randomised patients are drawn from similar populations with reference to their risk profile for the various time-to-event outcomes measured [PFS, OS, postprogression survival (PPS) and time-to-treatment discontinuation]. In Chapter 4, Indirect comparison feasibility assessment, the non-equivalence of PFS data from the placebo arms of the two clinical trials has been clearly demonstrated. This is of crucial importance to attempts to employ relative effectiveness measures reliant on the PHs assumption in relation to PFS, which is the only standard outcome variable reported in these trials that is free from any contamination by crossover effects (both trial protocols required confirmation of disease progression before patients were allowed to enter the open-label phase in which patients in the placebo arm were offered crossover treatment).

The problem of devising a credible approach to indirect comparison between lenvatinib and sorafenib for PFS cannot be resolved by appeal to technical argument alone. The pattern of hazard over time for disease progression in the two active arms is sufficiently similar to justify a simple HR approach. However, the placebo arms exhibit unexpectedly inconsistent patterns of temporal change, not compatible with the assumption of similarity between the patient groups not receiving active treatment. The AG, therefore, considers that the patients enrolled in the two trials cannot be considered to derive from a common population. This degree of difference precludes the use of either placebo arm as being representative of untreated patients across both trials.

The data for both placebo arms exhibit an unexpected improvement in long-term survival (reducing progression hazard) for which there is no obvious explanation. The effect of this phenomenon is to produce a varying differential in performance when comparing survival components across the two trials without any clear confirmatory evidence. Therefore, the AG is unable to support the use of a conventional ITC in this appraisal. The AG considers that it is preferable to model the relative effectiveness and cost-effectiveness of each active treatment against its own placebo comparator, and then generate results for each drug relative to the placebo of the other clinical trial as a sensitivity analysis, in order to allow assessment of the uncertainty associated with the choice of comparator.

Progression-free survival

The AG chose to use data for locally assessed PFS rather than centrally assessed PFS, as local assessment is generally more closely related to normal clinical practice.

Lifetime mean PFS for patients in DECISION who received placebo may be readily estimated from trial data (for the period available) and a simple exponential curve that conforms closely to the reported trial data (Figure 11). The AG estimated lifetime mean PFS from the area under the K–M data to 16.5 months of elapsed time followed by the area under the exponential function thereafter, giving a lifetime mean PFS estimate of 7.56 months. The sorafenib PFS arm of DECISION exhibits a simple constant hazard (exponential) relationship (see Figure 11), allowing the lifetime mean PFS to be estimated in a similar fashion, using the area under the curve (AUC) of the K–M data until 25 months, and the exponential extrapolation thereafter. This shows a lifetime mean PFS estimate of 47.18 months for patients receiving sorafenib, and a mean gain in PFS of 39.62 months compared with receiving placebo.

FIGURE 11.

Progression-free survival K–M data from DECISION modelled by an exponential function.

The SELECT data for PFS exhibit a more complex pattern in each arm. The cumulative hazard plots (Figure 12) reveal two distinct phases, both of which follow a constant hazard. Patients in the placebo arm who remain progression-free after 312 days experience a reduction in hazard of about 53%, which is sustained thereafter. Similarly, patients in the lenvatinib arm experience a reduction of progression hazard of about 47% at 529 days. As before, the estimated mean lifetime PFS for these patient groups was estimated as the sum of the AUC in each trial arm, followed by lifetime extrapolation using the long-term exponential hazard of progression or death. This approach yields estimates of mean lifetime PFS of 41.00 months for patients receiving lenvatinib and 6.92 months for patients in the placebo arm of SELECT. Thus, the estimated net lifetime gain in PFS for patients receiving lenvatinib is estimated to be 34.08 months.

FIGURE 12.

Cumulative hazard for disease progression for SELECT, with two-phase fitted exponential models.

Time to treatment discontinuation

As illustrated in Figure 13, the SELECT data are virtually complete for the cycles of lenvatinib dispensed during the trial. The AG estimates mean usage of lenvatinib as 12.61 30-day cycles per patient.

FIGURE 13.

The 30-day cycles of lenvatinib dispensed in SELECT.

The DECISION trial data are also complete for the cycles of sorafenib dispensed during the trial, as illustrated in Figure 14. The AG estimates mean usage of sorafenib as 14.36 28-day cycles per patient.

FIGURE 14.

The 28-day cycles of sorafenib dispensed in DECISION.

Overall survival

Data provided by the company for lenvatinib-treated patients in SELECT (Figure 15) show a simple long-term exponential trend indicating a constant mortality risk throughout the trial period (19.6% per year). This allows the mean lifetime OS for patients treated with lenvatinib to be estimated using the AUC of the trial K–M curve until 34.7 months plus a simple exponential extrapolation thereafter, giving a total mean OS of 55.1 months.

FIGURE 15.

Overall survival: lenvatinib-treated patients in SELECT with a fitted exponential model, and RPSFTM adjusted for placebo patient crossover with a long-term exponential-fitted model.

Both companies have employed RPSFTM adjustments to data from the placebo arms of their clinical trials to correct for patients crossing over to the active treatment following disease progression. Adjusted OS placebo arm data from SELECT are also displayed in Figure 15 and indicate that, after RPSFTM adjustment, a similar long-term exponential (constant risk) trend also applies to the placebo arm beyond 6 months. Using the AUC of the adjusted K–M curve until 19.1 months plus the exponential extrapolation thereafter yields a lifetime estimated mean OS for the corrected placebo arm of 29.9 months and a net estimated OS gain attributable to treatment with lenvatinib of 25.3 months.

An examination of the OS data from DECISION (Figure 16) indicates that both patients in both treatment arms were subject to a period of relatively low mortality hazard, followed by transition to a higher constant risk of death. This transition took place after 11.2 months for sorafenib patients and 6.4 months for placebo patients.

FIGURE 16.

Cumulative mortality hazard for sorafenib-treated patients in DECISION with a fitted two-phase exponential model, and for RPSFTM-adjusted placebo patients with a fitted two-phase exponential model.

Using the AUC of the RPSFTM-adjusted K–M curve for the placebo arm until 6.4 months plus the AUC of the exponential extrapolation thereafter yields a lifetime estimated mean OS for the placebo arm of 47.18 months. Similarly, combining the AUC of the sorafenib arm up to 11.96 months with the exponential trend thereafter yields an estimated lifetime mean OS of 56.66 months. Thus, the net mean OS gain attributable to sorafenib is 9.48 months.

Postprogression survival

Assessment of PPS may be carried out at an aggregate level by calculating the difference between model estimates of OS and PFS. However, it can also be informative to consider this outcome at the level of individual patients, at which it may provide useful insight into possible post-treatment long-term effects of treatments even after active treatment has ceased. The AG asked both companies to provide PPS data from their respective primary clinical trials. Unfortunately, only data from SELECT have been received. As with OS, it is important to allow for the effects of crossover on PPS by using RPSFTM-adjusted data.

In Figure 17, the beneficial effect of crossover to lenvatinib for patients initially randomised to the placebo arm is clearly apparent. Both trial arms exhibit a similar early pattern, albeit at different absolute levels of survival, and thereafter show similar long-term exponential trends after 15 to 18 months from the time of disease progression. When the RPSFTM adjustment is applied, the corrected placebo arm very closely follows the trajectory of the lenvatinib arm (although the effect of RPSFTM revised censoring does not allow direct comparison beyond 16 months). Nonetheless, these data suggest that, after crossover adjustment, there is probably no additional benefit to individual patients crossing from placebo to lenvatinib beyond what would have been gained by treatment prior to disease progression.

FIGURE 17.

Postprogression survival: lenvatinib in SELECT with a fitted exponential model, and RPSFTM adjusted for placebo patient crossover with a long-term exponential-fitted model.

Summary of time-to-event outcome data analysis

Estimates of PFS, OS and PPS and mean cycles of active treatment received in the two clinical trials are displayed in Table 22. The main difference occurs in the PFS results in which lenvatinib provides substantially greater benefit than sorafenib (34.1 additional months before progression compared with only 6.3 months, respectively). However, the estimated OS results are very similar (55.1 for lenvatinib vs. 56.8 months for sorafenib), and, consequently, estimated PPS is reduced with lenvatinib treatment but increased for sorafenib treatment). Thus, it appears that lenvatinib shows effect more strongly in initially delaying progression, but does not offer additional benefit over sorafenib in terms of long-term survival. The duration of active treatment in the two trials is very similar when measured in days rather than cycles, with a difference of < 7%.

TABLE 22 - The AG estimated mean time-to-event outcome variables

N/A, not applicable; TTD, time to treatment discontinuation.

RPSFTM adjusted for crossover in placebo arms.

Study, treatment arm	PFS (months)	OS (months)	PPS (months)	TTD (cycles)
SELECT
Lenvatinib	41.0	55.1	14.1	12.6 (30-day cycle)
Placebo	6.9	30.2a	23.3	N/A
Change attributable to lenvatinib	+ 34.1	+ 24.9	–9.2	N/A
DECISION
Sorafenib	13.8	56.8	42.9	14.4 (28-day cycle)
Placebo	7.6	43.8a	36.2	N/A
Change attributable to sorafenib	+ 6.3	+ 13.0	+ 6.7	N/A

Probabilistic sensitivity analyses

The AG carried out PSA varying model parameters subject to quantifiable stochastic sampling uncertainty:

• nine routine care cost variables

• seven AE incidence rates

• seven health-related utility values

• seven end-of-life health and social care costs.

In most cases, probabilistic values were drawn from normal distributions around the standard error of the mean, except for incidence rates, for which beta distributions were employed.

Using list prices, the in-trial comparisons of lenvatinib and BSC (Figure 18) and of sorafenib and BSC (Figure 19) yielded similar deterministic and probabilistic ICERs per QALY gained.

FIGURE 18.

Probabilistic sensitivity analysis: lenvatinib vs. BSC in SELECT.

FIGURE 19.

Probabilistic sensitivity analysis: sorafenib vs. BSC in DECISION.

Unfortunately, information relating to the key outcome variables (PFS, OS and time to treatment discontinuation) provided to the AG by one of the companies was not in the form requested, and information on uncertainty in the estimated treatment dose intensity was not included by the other company in its submission or their model. Without these key data items, it was not possible to incorporate these important components of the normal PSA on this occasion. Therefore, the results presented below should be treated with caution.

For the comparison of lenvatinib with BSC, the deterministic ICER is £65,872 per QALY gained and the probabilistic ICER is £66,038 per QALY gained.

For the comparison of sorafenib with BSC, the deterministic ICER is £85,644 per QALY gained and the probabilistic ICER is £83,547 per QALY gained.

The variation in additional cost per patient is much smaller relative to the uncertainty in outcomes (QALYs) gained because of the dominance of drug acquisition costs, which constitute 85–90% of the incremental cost per patient when full list prices are assumed to apply.

Clearly, both treatments exhibit estimated ICERs well above £50,000 per QALY gained if list prices are applied. This is confirmed by the cost-effectiveness acceptability curves (CEACs) presented in Figures 20 and 21. An examination of the CEACs shows that, compared with BSC, the probability of sorafenib being cost-effective at a threshold of £50,000 per QALY gained is < 0.05% and the probability of lenvatinib being cost-effective is 5.4%.

FIGURE 20.

Cost-effectiveness acceptability curves for sorafenib vs. BSC (DECISION).

FIGURE 21.

Cost-effectiveness acceptability curves for lenvatinib vs. BSC (SELECT).

Statement of principal findings

Strengths and limitations of the assessment

Other relevant factors

The AG considers that it is important to reiterate that the cost–utility analyses presented in this MTA report are based on list prices only. As lenvatinib has a confidential PAS price and sorafenib has a confidential Commercial Unit Access price, the cost-effectiveness comparisons presented in this AG report cannot be used as the basis for decision-making. The AG provided cost-effectiveness results generated using the discounted prices for lenvatinib and sorafenib in a confidential appendix presented to NICE.

Suggested research priorities

In order of priority, the AG suggests the following further research priorities:

1. Head-to-head RCT evidence.

   1. Clinical advice to the AG is that only RR-DTC patients experiencing symptoms, or those who have clinically significant progressive disease, are likely to be treated in routine clinical practice. Subgroup analyses suggest that the effects on PFS are similar for patients treated with sorafenib regardless of whether they are symptomatic or asymptomatic. However, these findings are post hoc and include only a minority of symptomatic patients. It is unclear if other outcomes, such as OS, ORR, AEs and HRQoL, differ by symptomatic or asymptomatic disease. Future studies of patients should aim to include a greater proportion of patients with symptomatic disease and investigate possible differences. Consideration should be given to using the classification of patients as symptomatic or asymptomatic as a randomisation stratification factor.

   2. It would be useful to record, and report, HRQoL outcomes from any future clinical study of lenvatinib and sorafenib. In particular, data should be collected, using the EQ-5D questionnaire, throughout the whole trial period, not only from patients whose disease has not progressed. Further research on HRQoL from treating patients who have symptomatic disease compared with those who do not is also required.

   3. Currently, evidence does not allow a comparison of the effectiveness of treatment with lenvatinib with the effectiveness of treatment with sorafenib. A head-to-head trial considering these treatments and placebo would generate results that would be valuable to decision-makers.

   4. It would be useful to explore how lenvatinib, sorafenib and BSC should be positioned in the treatment pathway.

2. Statistical research.

   1. The AG considers that it is important to explore more than just standard differences in participant and trial characteristics when considering the heterogeneity of studies that may be included in an indirect comparison. The AG suggests that, before undertaking an indirect comparison, the risk profiles of patient populations for the relevant outcome should be checked to confirm that they are proportional both within and across all trials that are being considered for inclusion in the network. This assessment would avoid generating indirect comparison results that are of unknown reliability.

Contributions of authors

Nigel Fleeman (Research Fellow, University of Liverpool) reviewed the evidence for clinical effectiveness, including study selection, data extraction, synthesis and interpretation. He contributed to the study selection for inclusion into the cost-effectiveness review and provided editorial input.

Rachel Houten [Research Associate (Health Economics Modelling), University of Liverpool] reviewed the evidence for cost-effectiveness, including study selection, data extraction, synthesis and interpretation. She contributed to the study selection for inclusion into the clinical effectiveness review and developed cost models for routine treatment and AEs.

Adrian Bagust (Professor of Health Modelling, University of Liverpool) developed the de novo economic model.

Marty Richardson [Research Associate (Medical Statistician), University of Liverpool] provided statistical advice and quality assessment of the systematic reviews included in the clinical effectiveness review.

Sophie Beale [Research Associate (Decision Analyst), University of Liverpool] interpreted the clinical effectiveness and cost-effectiveness evidence, summarised the company economic models and provided editorial input.

Angela Boland (Associate Director, University of Liverpool) interpreted the clinical effectiveness and cost-effectiveness evidence and provided editorial input.

Yenal Dundar (Research Fellow, University of Liverpool) contributed to data extraction and the quality assessment of studies included in the clinical effectiveness review.

Janette Greenhalgh [Senior Research Fellow (Clinical Effectiveness), University of Liverpool] contributed to data extraction and the quality assessment of studies included in the clinical effectiveness review.

Juliet Hounsome (Research Associate, University of Liverpool) contributed to the protocol development and the selection of studies for inclusion into the clinical effectiveness review.

Rui Duarte (Health Technology Assessment Lead, University of Liverpool) provided editorial input.

Aditya Shenoy (Consultant in Clinical Oncology, The Clatterbridge Cancer Centre NHS Foundation Trust) provided clinical advice on all aspects of the review.

All authors contributed to the writing of the report.

Publication

Fleeman N, Houten R, Chaplin M, Beale S, Boland A, Dundar Y, et al. A systematic review of lenvatinib and sorafenib for treating progressive, locally advanced or metastatic, differentiated thyroid cancer after treatment with radioactive iodine. BMC Cancer 2019;19;1209.

Data-sharing statement

All data requests should be submitted to the corresponding author for consideration. Access to anonymised data may be granted following review.

Disclaimers

This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care.

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