Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
Pembrolizumab shows moderate benefit over current care, with significant improvement in overall survival (10.1 months vs. 6.2 months for UK SoC) but no improvement in progression-free survival. The evidence is based on the KEYNOTE-045 trial, which is a well-conducted RCT, but the overall survival benefit is modest.
Cost effectiveness
The most plausible ICER for pembrolizumab is likely over £50,000 per QALY gained, which is above the threshold typically considered acceptable by NICE. The uncertainty in the cost-effectiveness estimates and the need for price justification indicate low cost-effectiveness.
Quality of life
The evidence indicates that pembrolizumab is well tolerated and associated with fewer severe adverse events compared to chemotherapy, suggesting a moderate improvement in quality of life. However, specific HRQoL data from validated instruments is not detailed in the document.
Supporting Domains
Safety and Adverse Effects
Pembrolizumab has a very good safety profile, with mostly mild or moderate adverse events and fewer severe adverse events compared to chemotherapy. This suggests a favorable tolerability profile.
Comparator Selection
The comparators used in the clinical trials (docetaxel and paclitaxel) are appropriate; however, there is no direct evidence comparing pembrolizumab with best supportive care, which limits the robustness of the evidence.
Patient Population and Subgroups
The trial population is representative of the intended patient population, with a focus on those who have received prior platinum-containing chemotherapy. However, there are some limitations in subgroup analyses.
Care Pathway Integration
Pembrolizumab can be integrated into existing care pathways with minor adjustments, as it fits within the current treatment landscape for urothelial carcinoma.
Resource Use and Cost Implications
The budget impact of pembrolizumab is significant, with costs likely underestimated in the model. The potential for high resource burden raises concerns about affordability.
Evidence Quality and Robustness
The evidence is based on a strong pivotal trial (KEYNOTE-045) with minor limitations. The trial design is robust, and the results are supported by additional analyses, although some uncertainties remain.
Uncertainty, Sensitivity, and Broader Impacts
There is significant uncertainty regarding the treatment effect duration and cost-effectiveness estimates, which may restrict the use of pembrolizumab. The context of unmet need is acknowledged but does not fully mitigate the uncertainties.
