Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The evidence from the CLEAR trial indicates that lenvatinib plus pembrolizumab provides a significant progression-free survival benefit compared to sunitinib, with overall survival gains noted in the intermediate- and poor-risk subgroups. However, the results for the favourable-risk subgroup are less certain, which prevents a higher rating.
Cost effectiveness
The cost-effectiveness estimates for lenvatinib plus pembrolizumab are acceptable when compared to nivolumab plus ipilimumab in the intermediate- and poor-risk subgroup, with an ICER around £20,000 per QALY gained, which is defensible despite some uncertainty.
Quality of life
The use of EQ-5D-3L data from the CLEAR trial to estimate utility values suggests moderate improvements in health-related quality of life, particularly for long-term survivors. The time-to-death approach used in the economic model is deemed appropriate, reflecting the health-related quality of life of patients effectively.
Supporting Domains
Safety and Adverse Effects
The safety profile of lenvatinib plus pembrolizumab is considered very good, with mostly mild to moderate adverse events reported in the CLEAR trial. Serious adverse events are rare, indicating a favorable tolerability compared to existing therapies.
Comparator Selection
The CLEAR trial compared lenvatinib plus pembrolizumab directly with sunitinib, which is a relevant standard of care. The committee also recognized nivolumab plus ipilimumab as an appropriate comparator for intermediate- and poor-risk patients, supporting the robustness of the comparator selection.
Patient Population and Subgroups
The trial population is representative of the intended patient population, with a balanced distribution across risk subgroups. However, some limitations exist in subgroup analyses, particularly for the favourable-risk group, which affects the overall generalizability.
Care Pathway Integration
Lenvatinib plus pembrolizumab can be integrated into existing treatment pathways with minor adjustments, as it aligns with current clinical practices for advanced renal cell carcinoma, particularly for intermediate- and poor-risk patients.
Resource Use and Cost Implications
The economic model indicates a manageable budget impact, particularly when considering the commercial arrangements for lenvatinib and pembrolizumab. The cost implications are justifiable given the expected benefits in the appropriate patient populations.
Evidence Quality and Robustness
The evidence base is strong, primarily derived from a Phase 3 RCT (CLEAR trial) with a well-structured design. However, some methodological concerns and uncertainties in subgroup analyses exist, which slightly diminish the robustness.
Uncertainty, Sensitivity, and Broader Impacts
While there are uncertainties regarding the long-term effects and the validity of some extrapolations, the context of unmet need and the potential benefits for patients with intermediate- and poor-risk disease provide a supportive backdrop for decision-making.
