Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical trial evidence from the KEYNOTE-859 trial demonstrates that pembrolizumab plus doublet chemotherapy significantly improves both progression-free survival and overall survival compared to placebo plus doublet chemotherapy in patients whose tumors express PD-L1 with a CPS of 1 or more. The hazard ratios indicate a clear clinical advantage, although the evidence for the CPS of 1 to 4 subgroup may overestimate effectiveness due to the inclusion of patients with higher CPS scores.
Cost effectiveness
The cost-effectiveness estimates for pembrolizumab plus doublet chemotherapy are within the acceptable range that NICE considers for Healthcare resources, particularly for the CPS of 1 or more subgroup. The committee noted that the ICERs were between £20,000 and £30,000 per QALY gained, which is defensible.
Quality of life
The evidence suggests that pembrolizumab plus doublet chemotherapy improves quality of life by delaying disease progression and increasing response rates, which are critical for symptomatic relief. However, specific HRQoL data from validated instruments is limited, indicating moderate improvements.
Supporting Domains
Safety and Adverse Effects
The safety profile of pembrolizumab is comparable to that of nivolumab, with manageable adverse events. The clinical expert confirmed that adverse events related to both treatments are similar and manageable, indicating a very good tolerability.
Comparator Selection
The treatment was compared against appropriate standard-of-care alternatives, including doublet chemotherapy and nivolumab plus doublet chemotherapy. The committee agreed that these comparators were relevant for the evaluation, although direct comparisons were not available.
Patient Population and Subgroups
The trial population is broadly representative of the intended patient population, particularly for those with a CPS of 1 or more. However, there are some concerns regarding the generalizability of results to the CPS of 1 to 4 subgroup due to potential overestimation of effectiveness.
Care Pathway Integration
Pembrolizumab can be integrated into existing treatment pathways with minor adjustments. The committee noted that it fits well within current clinical practices, requiring no significant new infrastructure or training.
Resource Use and Cost Implications
The budget impact is manageable, and the treatment is expected to be resource-efficient, particularly given the commercial arrangement that provides a discount. The committee concluded that the costs are justifiable relative to the benefits.
Evidence Quality and Robustness
The evidence is based on a robust Phase 3 RCT (KEYNOTE-859) with a low risk of bias. However, there are some limitations regarding subgroup analyses and the potential for overestimation of treatment effects, which slightly weaken the overall robustness.
Uncertainty, Sensitivity, and Broader Impacts
While there is some uncertainty regarding the treatment effect in the CPS of 1 to 4 subgroup, the overall context supports the use of pembrolizumab. The committee acknowledged the unmet need for this subgroup, which mitigates some of the uncertainty.
