Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
Pembrolizumab shows moderate clinical benefit over standard chemotherapy, with a statistically significant improvement in pathological complete response (63.0% vs. 55.6%) and event-free survival (83.5% vs. 74.9%). However, the overall survival benefit is not statistically significant, indicating that while there are improvements in key outcomes, the margin of benefit is modest.
Cost effectiveness
The cost-effectiveness estimates for pembrolizumab are likely within acceptable thresholds for Healthcare resources, with the committee concluding that it is likely to be cost-effective based on the economic model presented, despite some uncertainties.
Quality of life
The treatment is associated with improved quality of life due to less invasive surgical options resulting from higher rates of pathological complete response. The psychological benefits of achieving a complete response are emphasized, suggesting moderate improvements in HRQoL.
Supporting Domains
Safety and Adverse Effects
While there are additional adverse events associated with pembrolizumab, the clinical experts and patient feedback indicate that these are manageable and that the potential benefits outweigh the risks. The overall safety profile is considered very good.
Comparator Selection
The comparator used in the KEYNOTE-522 trial (chemotherapy plus placebo) is appropriate and reflects standard care practices, although there are some concerns about the specific chemotherapy agents used. Overall, the trial design supports the relevance of the comparator.
Patient Population and Subgroups
The trial population is broadly representative of the intended patient population in the Healthcare, with a diverse demographic and relevant subgroup analyses. The generalizability of the results to UK clinical practice is supported by the trial’s design.
Care Pathway Integration
Pembrolizumab can be integrated into existing treatment pathways with minor adjustments, as it is intended to be used alongside standard chemotherapy. The committee noted that practice would change to include this treatment, indicating a good fit.
Resource Use and Cost Implications
The budget impact is manageable, and there are potential cost savings associated with reduced invasive surgeries due to higher rates of pathological complete response. The overall resource use is considered justifiable given the benefits.
Evidence Quality and Robustness
The evidence is based on a robust Phase III trial (KEYNOTE-522) with a large sample size (n=1,174) and a well-structured design. While there are some limitations, the overall quality of evidence is strong.
Uncertainty, Sensitivity, and Broader Impacts
There is some uncertainty regarding long-term outcomes and the generalizability of subgroup results, but the context of unmet need and the potential benefits of treatment provide a favorable backdrop for decision-making.
