Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical trial evidence from KEYNOTE-671 shows that pembrolizumab combined with chemotherapy significantly improves event-free survival (EFS) and overall survival (OS) compared to placebo. The hazard ratios indicate a clear clinical advantage, with a statistically significant improvement in both EFS and OS. However, the lack of direct comparison with neoadjuvant nivolumab limits the strength of the evidence.
Cost effectiveness
The cost-effectiveness estimates for pembrolizumab fall within the acceptable range for Healthcare resources, with an ICER around £20,000 per QALY gained. This suggests that the therapy is marginally cost-effective, although the committee noted uncertainties that could affect the robustness of this conclusion.
Quality of life
The evidence indicates that pembrolizumab treatment leads to improvements in health-related quality of life, as reflected in utility values derived from the KEYNOTE-671 trial. However, the data on HRQoL is not comprehensive and relies on indirect comparisons, which introduces some uncertainty.
Supporting Domains
Safety and Adverse Effects
Pembrolizumab has a favorable safety profile, with mostly mild to moderate adverse events reported. Serious adverse events are rare, and the overall tolerability is good compared to existing therapies. This supports a strong safety rating.
Comparator Selection
The main comparator, neoadjuvant nivolumab, is appropriate; however, the absence of direct head-to-head trials with this comparator introduces uncertainty. The committee acknowledged that while indirect comparisons were made, they do not provide the same level of confidence as direct comparisons.
Patient Population and Subgroups
The trial population in KEYNOTE-671 is generally representative of the intended patient population, although there are some concerns regarding age differences. The committee noted that the mean age in the trial was lower than that typically seen in clinical practice, which could affect generalizability.
Care Pathway Integration
Pembrolizumab can be integrated into existing treatment pathways with minor adjustments, such as additional diagnostics. The committee noted that the treatment fits well within the current clinical practice for NSCLC.
Resource Use and Cost Implications
The budget impact of pembrolizumab is manageable, and the therapy is expected to be resource-efficient. The committee concluded that the overall resource use aligns with the expected benefits, although there are concerns about the long-term sustainability of costs.
Evidence Quality and Robustness
The evidence base is primarily derived from a well-conducted Phase III trial (KEYNOTE-671), which provides strong support for the therapy. However, the reliance on indirect comparisons and the absence of direct evidence against the main comparator introduce some limitations.
Uncertainty, Sensitivity, and Broader Impacts
There are notable uncertainties regarding the long-term effectiveness and generalizability of the trial results to the broader patient population. The committee highlighted concerns about the assumptions made in the economic model, particularly regarding treatment effect waning and cure assumptions.
