Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The evidence from the FLAURA2 trial indicates that osimertinib with pemetrexed and platinum-based chemotherapy significantly improves progression-free survival (PFS) compared to osimertinib alone, with a hazard ratio of 0.62 (95% CI 0.49 to 0.79, p<0.001). Although overall survival data is still uncertain, the interim analysis suggests a benefit (HR 0.75, 95% CI 0.57 to 0.97). This indicates a clear clinical advantage, justifying the A+ rating.
Cost effectiveness
The cost-effectiveness estimates for osimertinib with chemotherapy fall within the acceptable range for Healthcare resources, with the committee concluding that the most plausible ICER is around £20,000 to £30,000 per QALY gained. This indicates that the treatment is marginally cost-effective, justifying an A rating.
Quality of life
The trial included health-related quality of life as a secondary outcome, and while the exact utility values are confidential, the committee noted that the addition of chemotherapy may negatively impact quality of life. However, the overall improvements in PFS and the need for additional treatment options suggest a moderate benefit in HRQoL, justifying an A rating.
Supporting Domains
Safety and Adverse Effects
The safety profile of osimertinib with chemotherapy is generally acceptable, with manageable adverse events reported. While there are concerns about the additional adverse effects from chemotherapy, the overall tolerability remains good, leading to a rating of A+.
Comparator Selection
The clinical trial compared osimertinib with chemotherapy against osimertinib monotherapy, which is the current standard of care. This direct comparison strengthens the evidence base and supports the A+ rating.
Patient Population and Subgroups
The trial population is broadly representative of the intended patient population with untreated EGFR mutation-positive NSCLC. However, there are concerns regarding the generalizability of results due to the higher proportion of patients with CNS metastases in the trial compared to typical Healthcare practice, justifying an A rating.
Care Pathway Integration
Osimertinib with chemotherapy can be integrated into existing treatment pathways with some adjustments. The need for additional monitoring and potential changes in treatment protocols indicates moderate pathway changes, justifying an A rating.
Resource Use and Cost Implications
The economic model indicates that the resource use associated with osimertinib with chemotherapy is manageable and aligns with Healthcare planning. The committee concluded that the budget impact is acceptable, leading to an A+ rating.
Evidence Quality and Robustness
The evidence is based on a robust Phase 3 trial (FLAURA2) with a well-defined methodology. While there are some uncertainties regarding long-term outcomes, the overall quality of evidence supports an A rating.
Uncertainty, Sensitivity, and Broader Impacts
There are notable uncertainties regarding the extrapolation of overall survival and treatment duration, which could impact the cost-effectiveness results. The committee acknowledged these uncertainties, leading to a B++ rating.
