NICE Issues Technology Appraisal Guidance on Lenvatinib with Everolimus for Previously Treated Advanced RCC

Lenvatinib is indicated in combination with everolimus for the treatment of adult patients with advanced RCC following one prior VEGF-targeted therapy

On 24 January 2018, the NICE published evidence-based recommendations on lenvatinib (Kisplyx, Eisai) with everolimus for previously treated advanced renal cell carcinoma (RCC) in adults. Lenvatinib plus everolimus is recommended as an option for treating advanced RCC in adults who have had 1 previous vascular endothelial growth factor (VEGF)-targeted therapy, only if their Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1 and the company provides lenvatinib with the discount agreed in the patient access scheme.

This recommendation is not intended to affect treatment with lenvatinib plus everolimus that was started in the NHS before this guidance was published. Patients having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.

In the NHS, advanced RCC that has progressed after 1 tyrosine kinase inhibitor is treated with axitinib, nivolumab or cabozantinib.

The main clinical evidence for lenvatinib plus everolimus came from HOPE 205, a small open-label phase II randomised controlled trial comparing 3 treatments: lenvatinib plus everolimus (n=51), lenvatinib alone (n=52) and everolimus alone (n=50). The trial did not allow crossover. The appraisal committee agreed that it would focus on the comparison of lenvatinib plus everolimus with everolimus alone because lenvatinib alone was not licensed for advanced RCC. The primary outcome in the trial was investigator-assessed progression-free survival (PFS), with overall survival (OS), tumour response and safety as secondary outcomes. The PFS by independent review was assessed post hoc following a request from the regulators.

In HOPE 205, lenvatinib plus everolimus increased median PFS in the intention-to-treat population by 9.1 months compared with everolimus alone (14.6 months compared with 5.5 months; hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.24 to 0.68; p=0.0005). The appraisal committee noted that PFS assessed post hoc by independent review was similar, though the difference between the treatment groups was smaller; median PFS was 12.8 months with lenvatinib plus everolimus and 5.6 months with everolimus alone, corresponding to a difference of 7.2 months (HR 0.45, 95% CI 0.26 to 0.79; p=0.003).

The OS was based on the latest data cut of July 2015 (a median follow-up of 32.0 months for lenvatinib plus everolimus and of 32.7 months for everolimus alone). Patients who had lenvatinib plus everolimus lived longer than those who had everolimus alone (median survival 25.5 months versus 15.4 months; HR 0.59, 95% CI 0.36 to 0.97, based on the stratified Cox proportional hazard model). The p value using the stratified log-rank test was 0.065, which the appraisal committee recognised reflected statistically weak evidence on the survival benefit with lenvatinib plus everolimus. However, it was aware that HOPE 205 was not powered to detect statistically significant differences in terms of OS between treatment groups.

The appraisal committee considered the safety profile of lenvatinib plus everolimus, noting that serious adverse events occurred in a higher proportion of patients taking lenvatinib plus everolimus (54.9%) than in patients taking everolimus alone (42.0%). In the lenvatinib plus everolimus group, 72.5% of patients had grade III or higher treatment-emergent adverse events, compared with 54.0% of patients taking everolimus alone. A larger proportion of patients had dose interruptions of lenvatinib (80.4%) or everolimus (76.5%) in the lenvatinib plus everolimus group compared with the everolimus alone group (54.0%), mainly because of adverse events.

Because there were no head-to-head trials comparing lenvatinib with axitinib, nivolumab or cabozantinib, the company compared the treatments indirectly using a network meta-analysis. It included the randomised controlled trials HOPE 205, CHECKMATE-025 and METEOR (lenvatinib plus everolimus, nivolumab and cabozantinib respectively, each compared with everolimus), and estimated OS and PFS curves for each treatment using fractional polynomials. In doing so, the company assumed that axitinib was as effective as everolimus with respect to OS and PFS, which the appraisal committee recalled it had accepted in previous technology appraisals as a reasonable assumption in this therapy area. The appraisal committee concluded that the company's network using fractional polynomials was appropriate for decision-making.

The recommended daily dose of lenvatinib is 18 mg (1×10 mg capsule and 2×4 mg capsules) once daily, with 5 mg of everolimus once daily.

The cost-effectiveness analyses for lenvatinib plus everolimus show it's more effective and less costly than cabozantinib and nivolumab. Compared with axitinib, the cost-effectiveness estimates are within what NICE normally considers acceptable.

The list price of lenvatinib is 1,437.00 GBP per 30‑capsule pack (4 mg and 10 mg).

The list price of everolimus is 2,250.00 GBP per 30‑tablet pack of 5 mg everolimus.

The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of lenvatinib, with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.