Conclusions

Compared with placebo, treatment with lenvatinib or sorafenib results in an improvement in PFS, ORR and, possibly, OS. However, compared with placebo, both drugs also increase the incidence of AEs, in particular hypertension, hand–foot syndrome and diarrhoea. Dose reductions with both drugs are, therefore, frequently required.

The AG considers that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib with those of sorafenib. Primarily, this is because the risk profiles of the patients in the placebo arms of SELECT and DECISION do not appear to be comparable.

Using list prices, compared with BSC, both treatments exhibit estimated ICERs of > £50,000 per QALY gained. 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%.

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.