Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical evidence suggests that alpelisib plus fulvestrant may be more effective than everolimus plus exemestane based on indirect comparisons. However, the analyses are highly uncertain due to the lack of direct comparative data and reliance on a single-arm study (BYLieve) for the primary evidence. The committee noted that while BYLieve met its primary endpoint, the overall effectiveness remains uncertain due to the absence of robust comparative data.
Cost effectiveness
The cost-effectiveness estimates for alpelisib plus fulvestrant are uncertain but fall within the acceptable range for Healthcare resources. The committee concluded that the deterministic model indicated a plausible ICER comfortably below £50,000 per QALY gained, which is considered acceptable for a life-extending treatment.
Quality of life
There is limited HRQoL data available from the clinical trials, particularly after disease progression. The evidence suggests that while there may be some improvements in quality of life, the overall impact is not well-documented, and the potential for adverse effects may negatively influence HRQoL.
Supporting Domains
Safety and Adverse Effects
Alpelisib plus fulvestrant is associated with grade 3 or higher adverse events, which require additional monitoring. However, the overall safety profile is acceptable, and while there are notable adverse effects, they are manageable for many patients. The committee acknowledged the burden of these adverse events but concluded that they do not outweigh the potential benefits.
Comparator Selection
The primary comparator used in the economic model is everolimus plus exemestane, which is relevant for the patient population. However, the committee noted that the indirect treatment comparison used to assess effectiveness has significant uncertainties, which limits the robustness of the evidence.
Patient Population and Subgroups
The trial population in BYLieve is considered representative of the intended patient population with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer. The committee noted that the population studied aligns well with clinical practice in the UK.
Care Pathway Integration
Alpelisib plus fulvestrant can be integrated into existing treatment pathways with minor adjustments. The committee noted that the treatment fits well within the current clinical practice for patients who have progressed after a CDK4/6 inhibitor plus an aromatase inhibitor.
Resource Use and Cost Implications
The resource implications of alpelisib plus fulvestrant are manageable within the Healthcare framework. The committee concluded that the treatment represents a reasonable budget impact, especially considering the potential for cost-effectiveness in the context of life-extending treatments.
Evidence Quality and Robustness
The evidence base is primarily derived from a single-arm study (BYLieve) and an indirect treatment comparison, which raises concerns about robustness and potential biases. The committee noted that while the evidence is suggestive of effectiveness, it lacks the strength of multiple rigorous Phase III trials.
Uncertainty, Sensitivity, and Broader Impacts
There are significant uncertainties surrounding the treatment effects and cost-effectiveness estimates due to the reliance on indirect comparisons and limited data. The committee acknowledged these uncertainties but noted that the treatment addresses a significant unmet need in the patient population.
