Background
Thyroid cancer accounts for approximately 1% of all new malignancies in the United Kingdom (UK) [
1] and approximately 3% of all new malignancies in the United States (US) [
2]. Commonly asymptomatic and so often discovered incidentally [
3], the most common type of thyroid cancer is differentiated thyroid cancer (DTC). A review of 2936 US patients registered with DTC found papillary carcinoma (PTC), follicular carcinoma (FTC) and Hürthle cell carcinoma to constitute 86, 10 and 4% of cases respectively [
4]. Globally, DTC incidence is increasing [
5]. In part, this increase has been attributed to improved diagnostic and detection techniques [
6].
Surgery followed by daily oral medication (levothyroxine
) to suppress blood thyroid stimulating hormone (TSH) levels is the mainstay of treatment for DTC [
7‐
10]. Additional treatment in the form of radioactive iodine may be required for patients who develop local, regional or metastatic disease (5 to 20% patients [
7,
9]). For most patients, radioactive iodine treatment is effective. However, 5 to 15% [
4,
11‐
15] of people with DTC develop radioactive iodine refractory differentiated thyroid cancer (RR-DTC), i.e. they are unable to safely tolerate treatment or they develop DTC that has become resistant to treatment.
For patients with RR-DTC, treatment options have been limited. Chemotherapy is rarely or never recommended by the authors of clinical guidelines [
7‐
10] and thus, for many patients, best supportive care (BSC) has been the only treatment option. However, the authors of published clinical guidelines have noted the promise of targeted therapies including tyrosine kinase inhibitors (TKIs). Lenvatinib is the most recent TKI to be licensed for treating RR-DTC, receiving a licence in the US in February 2015 [
16] and in the European Union (EU) in May 2015 [
17]. The only other licensed TKI is sorafenib, which was licensed for the treatment of RR-DTC in the US in November 2013 [
18] and in the EU in January 2015 [
19]. The authors of the US National Comprehensive Cancer Network (NCCN) guidelines now recommend that lenvatinib and sorafenib should be considered for treating progressive and/or symptomatic RR-DTC [
10]. The authors, however, caution against their use for patients with stable or slowly progressive indolent disease [
10]. The authors of the American Thyroid Association (ATA) guidelines caution that patients who are candidates for TKI therapy “should be thoroughly counseled on the potential risks and benefits of this therapy as well as alternative therapeutic approaches including best supportive care” [
7]. Important risks associated with lenvatinib highlighted by regulatory agencies [
16,
17] include: hypertension; cardiac dysfunction; arterial thromboembolic events; hepatotoxicity, renal failure or impairment; proteinuria; diarrhea; fistula formation and gastrointestinal perforation; QT interval prolongation; hypocalcemia; reversible posterior leukoencephalopathy syndrome; hemorrhagic events; impairment of TSH suppression/thyroid dysfunction; wound healing complications; and embryo-fetal toxicity. Important risks associated with sorafenib highlighted by regulatory agencies [
18,
19] include: dermatologic toxicities including severe skin adverse events (AEs) and hand-foot syndrome; hypertension; posterior reversible encephalopathy syndrome; hemorrhage (including lung hemorrhage, gastrointestinal hemorrhage and cerebral hemorrhage); arterial thrombosis (myocardial infarction); congestive heart failure; QT interval prolongation; squamous cell cancer of the skin; gastrointestinal perforation; symptomatic pancreatitis and increases in lipase and amylase; hypophosphatemia; renal dysfunction; interstitial lung disease-like events; drug-induced hepatitis; impairment of TSH suppression; and embryo-fetal toxicity.
While lenvatinib and sorafenib are available for treating RR-DTC in several countries, the extent to which they are available to patients has varied. For example, lenvatinib and sorafenib are available for all patients who require these treatments in Scotland via the National Health Service (NHS) [
20,
21]. However, prior to August 2018, they were only available for patients in special circumstances in the NHS in England. In order to be routinely used in the NHS in England, a positive recommendation from the National Institute for Health and Care Excellence (NICE) is required. We, the Liverpool Reviews and Implementation Group (LRiG), were commissioned, in our capacity as an independent Assessment Group, to provide an independent review of the clinical and cost effectiveness evidence as part of a NICE multiple technology appraisal (MTA). In this paper, we report our systematic review of the clinical effectiveness evidence for lenvatinib and sorafenib and discuss how the evidence has impacted on NICE recommendations for clinical practice.
Discussion
The aim of this review was to compare the clinical effectiveness evidence for lenvatinib or sorafenib in relation to BSC and also to compare the effectiveness of both drugs with each other.
Trial results show that both drugs are more efficacious in terms of median PFS [
26,
27] and ORR [
26,
27] but also result in more AEs than placebo [
24,
27]. Placebo can be considered to be a proxy for BSC in both trials, even though concurrent use of palliative radiotherapy was not permitted for patients in the SELECT trial (data from CSR). Some of the most common types of AEs differ by drug, most notably hypertension being very common with lenvatinib [
24] and hand-foot syndrome being very common with sorafenib [
27]. We were unable to determine the true impact of lenvatinib and sorafenib on OS or how both drugs, particularly lenvatinib, impact upon HRQoL. This is because OS is confounded by treatment crossover in both trials [
26,
27] and HRQoL data is limited to reports of sorafenib from the DECISION trial [
25,
55].
It should however be noted that results for OS (except in the case of the DECISION trial), RPSFTM-adjusted OS and PFS described as statistically significant (or otherwise) should be interpreted with caution, since we found for that for these outcomes, the PH assumption was violated. It is therefore not possible to ascertain whether the HRs are overestimates or underestimates of the effect of the intervention versus placebo in either trial.
In conducting a feasibility assessment of performing indirect comparisons, we identified potential differences in trial and population characteristics at baseline. Since the PH assumption for OS and PFS data were also found to be violated, we considered that the validity of conducting an indirect comparison (matched or otherwise) using standard methods was questionable. Importantly, we also identified differences in the survival risk profiles of patients in the placebo arms of the trials. These differences may reflect known or unknown differences in trial and participant characteristics. The identification of these differences was our primary reason for considering an indirect comparison to be inappropriate. Of note, the CADTH have also considered the populations to be different, stating that the SELECT trial population had more aggressive disease as reflected by PFS in the placebo arms [
39]. Furthermore, in its consideration of the evidence base during the MTA process, the NICE Appraisal Committee agreed that the Kaplan-Meier plots for PFS in the placebo arms of the trials were sufficiently different to suggest there were important differences limiting the robustness of the indirect comparisons [
64].
NICE guidance is based on the recommendations of the NICE Appraisal Committee. The extent to which the findings from either of the SELECT and DECISION trials are generalizable to clinical practice was one of the key considerations for the NICE Appraisal Committee [
64]. In clinical practice, patients are often not treated with lenvatinib or sorafenib unless their disease is symptomatic, or they have clinically significant progressive disease (e.g. obvious radiological or biochemical progression). Data published in the EPAR for sorafenib [
56] indicate that approximately 20% of patients in the DECISION trial had been retrospectively defined as being symptomatic; the equivalent proportion in the SELECT trial was unknown. To be eligible for entry into both trials, patients were required to have had radiographic evidence of disease progression within the last 12 months (SELECT trial) or 14 months (DECISION trial) [
26,
27]. Arguably these eligibility criteria suggest that patients had clinically significant disease that was likely to be rapidly progressing, if left untreated. Indeed, clinical opinion presented to the NICE Appraisal Committee was that if patients were not yet symptomatic in the trials, it was likely they would soon become symptomatic [
64]. The evidence from both trials, even though it appears to include slightly different trial populations, was, therefore, considered to be generalizable to clinical practice.
In the absence of results from reliable indirect comparisons, findings from observational studies provide important supporting evidence. The magnitude of effects in relation to OS, PFS and the incidence of some AEs differed in prospective observational studies [
28‐
31,
33‐
36,
57,
59] and meta-analyses [
44,
45] to the RCT findings [
24‐
27]. There are a number of reasons that could explain this. First, as with the RCTs, differences in unknown patient characteristics may be contributory factors. Second, the differing lengths of follow-up should be considered. Third, all of the prospective observational studies were relatively small, and so the results are more prone to being influenced by any outlying cases. However, while caution needs to be exercised in comparing results across studies of different study populations, the combined evidence from RCTs [
26,
27] and observational studies [
28‐
31,
33‐
36,
59] suggests ORR may be higher for patients treated with lenvatinib than for patients treated with sorafenib. Evidence from observational studies [
28‐
31,
33,
35,
36,
57] and meta-analyses [
44,
45] also show that many common AEs reported with lenvatinib and sorafenib in the RCTs [
26,
27] are also experienced by patients treated with these drugs in other study populations. The evidence shows that some AEs are very common to both lenvatinib and sorafenib (e.g. diarrhoea), whereas other AEs tend to be more drug specific (e.g. hypertension with lenvatinib and hand-foot syndrome with sorafenib) [
28,
29,
33,
35,
36,
44,
45,
57]. Therefore, the body of evidence taken as a whole supports the NCCN recommendation that “The decision of whether to use lenvatinib (preferred) or sorafenib should be individualized for each patient based on likelihood of response and comorbidities” [
10].
No HRQoL data for lenvatinib are available from either the SELECT trial or the supporting observational studies, [
29,
36]. Only the DECISION trial collected HRQoL data for patients treated with sorafenib, and then only until the end of treatment [
25,
55]. In the DECISION trial, “mild” reductions in HRQoL were reported for patients treated with sorafenib compared to those receiving the placebo [
25,
55]. Given the different objective tumour response rates and types of AEs reported in the studies of lenvatinib, HRQoL data for patients treated with lenvatinib would have been very informative. It is unclear whether, for patients treated with lenvatinib, obtaining an objective response to treatment is associated with improved HRQoL, or if they too would experience “mild” reductions in HRQoL. The exploration of HRQoL associated with treatment with both drugs is an area requiring further research.
Another area where further research is required relates to the sequential use of lenvatinib and sorafenib. Subgroup analysis results from the SELECT trial suggest that differences in PFS, ORR and AEs for lenvatinib versus placebo were similar regardless of whether a patient had been previously treated with a TKI, or not [
26,
49,
50]. However, no OS evidence has been reported for these subgroups. Furthermore, the number of patients in these subgroups, particularly in the placebo arm, is small. Importantly, there is no evidence for the efficacy or safety of treatment with sorafenib following treatment with lenvatinib.
The evidence presented in our review has been used as the basis for making recommendations for practice in England. Guidance was issued by NICE in August 2018 [
64]. In drafting the guidance, the NICE Appraisal Committee considered the uncertainties identified in our review, alongside cost effectiveness evidence, and testimonies from clinical and patient experts. NICE guidance recommends the use of lenvatinib or sorafenib for treating RR-DTC if both drugs are provided at a discounted price [
64]. However, NICE guidance also includes the restriction that lenvatinib or sorafenib are only available to patients who have not previously received treatment with a TKI or “if they have had to stop taking a TKI within 3 months of starting it because of toxicity (specifically, toxicity that cannot be managed by dose delay or dose modification)” [
64]. The reason given for this restriction is because NICE considered that there is “not enough clinical evidence and no cost-effectiveness evidence to determine whether the treatments are effective when used sequentially” [
64]. Restricted use of lenvatinib or sorafenib differs to the licensing [
16‐
19] and also reimbursement approval received elsewhere in the UK [
21].
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.