Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The clinical trial evidence from DESTINY-Breast03 shows that trastuzumab deruxtecan significantly improves progression-free survival compared to trastuzumab emtansine, with a hazard ratio of 0.28 (p<0.001). However, overall survival data is still immature, and while there is a strong indication of clinical benefit, the lack of definitive long-term survival data limits the rating to A.
Cost effectiveness
The cost-effectiveness estimates for trastuzumab deruxtecan are highly uncertain due to immature overall survival data. The committee concluded that while there are plausible ICERs below £30,000 per QALY, the uncertainty surrounding long-term survival benefits means that the cost-effectiveness is not clearly established.
Quality of life
While the evidence suggests that trastuzumab deruxtecan may improve quality of life, particularly post-progression, there is no direct trial evidence to support a utility benefit. The committee noted that side effects could impact quality of life, but these are manageable. Thus, the impact on HRQoL is considered minimal or mixed.
Supporting Domains
Safety and Adverse Effects
Trastuzumab deruxtecan has a manageable safety profile, with side effects such as interstitial lung disease that can be monitored effectively. Clinical experts indicated that the side effects are acceptable given the potential benefits, leading to an acceptable safety rating.
Comparator Selection
The comparator, trastuzumab emtansine, is the current standard of care for patients who have received prior anti-HER2 treatments. The evidence is based on a relevant head-to-head comparison, which supports a strong rating.
Patient Population and Subgroups
The DESTINY-Breast03 trial included a diverse patient population, although the number of participants from England was low. The committee concluded that the trial population is generally representative of the intended patient population, leading to a moderate rating.
Care Pathway Integration
Trastuzumab deruxtecan can be integrated into existing treatment pathways with minor adjustments. The committee noted that it fits well within the current clinical practice for HER2-positive breast cancer treatment.
Resource Use and Cost Implications
The resource implications of trastuzumab deruxtecan are significant, and while it may be cost-effective under certain conditions, the high uncertainty in cost-effectiveness estimates raises concerns about its broader resource impact.
Evidence Quality and Robustness
The evidence base is primarily derived from a single pivotal Phase 3 trial, which, while robust, has limitations due to the immaturity of overall survival data. This leads to some concerns regarding the completeness and reliability of the evidence.
Uncertainty, Sensitivity, and Broader Impacts
There is significant uncertainty regarding the long-term outcomes and cost-effectiveness of trastuzumab deruxtecan. The committee acknowledged that while there is potential for further evidence to clarify these uncertainties, the current situation warrants a cautious approach.
