Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
Trastuzumab deruxtecan shows moderate benefit over current care, with statistically significant improvements in progression-free survival (hazard ratio 0.5) and overall survival (hazard ratio 0.6) compared to treatment of physician choice (TPC). However, the evidence is limited by the lack of direct comparison with sacituzumab govitecan, which introduces uncertainty about its relative effectiveness.
Cost effectiveness
The cost-effectiveness estimates for trastuzumab deruxtecan are above the acceptable range for Healthcare resources, with the most plausible ICER being around £30,000 per QALY gained. This indicates low cost-effectiveness, necessitating price justification.
Quality of life
The evidence indicates that trastuzumab deruxtecan may improve quality of life for patients with HER2-low metastatic breast cancer, as highlighted by patient organization submissions. However, the exact impact on HRQoL is not quantified in the document, leading to a moderate rating.
Supporting Domains
Safety and Adverse Effects
Trastuzumab deruxtecan has a very good safety profile, with mostly mild or moderate adverse events reported. Serious adverse events are rare, indicating a favorable tolerability compared to existing therapies.
Comparator Selection
The comparator in the DESTINY-Breast04 trial, treatment of physician choice, included options that may not fully reflect current Healthcare practice, such as the absence of sacituzumab govitecan. This raises concerns about the appropriateness of the comparator.
Patient Population and Subgroups
The trial population is considered broadly representative of the intended patient population in Healthcare practice, although there are some concerns regarding the age and fitness of participants compared to typical patients.
Care Pathway Integration
Trastuzumab deruxtecan is positioned as a second- or third-line treatment, which aligns well with existing treatment pathways for HER2-low metastatic breast cancer, requiring only minor adjustments for integration.
Resource Use and Cost Implications
The resource implications of adopting trastuzumab deruxtecan are significant, with concerns raised about the overall budget impact on the Healthcare. The committee noted that the ICERs were considerably higher than acceptable thresholds.
Evidence Quality and Robustness
The evidence base is supported by a well-conducted Phase III trial (DESTINY-Breast04) with a robust design, although there are some limitations regarding generalizability and the absence of direct comparisons with other treatments.
Uncertainty, Sensitivity, and Broader Impacts
There is high uncertainty surrounding the cost-effectiveness estimates, particularly regarding overall survival extrapolation and post-progression utility values. This uncertainty may restrict the use of trastuzumab deruxtecan.
