Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The TRANSFORM trial, a Phase 3 randomized open-label trial, demonstrated a statistically significant benefit for lisocabtagene maraleucel (liso-cel) in event-free survival (EFS) compared to standard care, with a hazard ratio of 0.38 (95% CI 0.26 to 0.54). However, the overall survival (OS) results were not statistically significant, and the committee noted uncertainties regarding the long-term survival outcomes due to a high crossover rate from standard care to liso-cel. Therefore, while there is moderate benefit shown in EFS, the uncertainty in OS limits the rating to A.
Cost effectiveness
The cost-effectiveness estimates for liso-cel were found to be within the acceptable range for Healthcare resources, with an ICER around £30,000 per QALY gained. The committee recognized that while there are uncertainties in the economic model, the potential for outpatient treatment and lower adverse event rates contribute positively to its cost-effectiveness. Thus, it is considered marginally cost-effective.
Quality of life
The evidence from the TRANSFORM trial indicated that liso-cel has the potential to improve quality of life due to a lower incidence of severe adverse events compared to standard care. The committee acknowledged that the treatment could be administered as an outpatient, which may further enhance HRQoL. However, the EQ-5D data completion rate was low, introducing some uncertainty. Overall, the evidence supports moderate improvements in HRQoL.
Supporting Domains
Safety and Adverse Effects
Liso-cel demonstrated a very good safety profile with significantly lower rates of grade 3 and 4 adverse events compared to standard care. The clinical experts noted that this safety profile is crucial for the quality of life of patients. While there are some adverse events associated with liso-cel, they are manageable and less frequent than those seen with standard treatments.
Comparator Selection
The committee concluded that standard care, which includes salvage chemotherapy and stem cell transplantation, was the appropriate comparator for liso-cel. However, the committee noted that axi-cel, another CAR-T therapy, was not a suitable comparator due to its restricted use in clinical practice. This limitation in comparator selection slightly undermines the robustness of the evidence.
Patient Population and Subgroups
The TRANSFORM trial included a well-defined population of adults with relapsed or refractory large B-cell lymphoma who were eligible for stem cell transplantation. The committee noted that the trial population closely reflects the intended real-world patient population, with minor gaps in subgroup analyses. Overall, the evidence is broadly generalizable.
Care Pathway Integration
Liso-cel can be integrated into existing care pathways with manageable adjustments, such as outpatient administration. The committee noted that while some changes to current practices may be necessary, these are not substantial and can be accommodated within the existing healthcare framework.
Resource Use and Cost Implications
The economic model indicated that liso-cel has a manageable budget impact, with potential cost savings associated with outpatient treatment and reduced adverse event management. The committee acknowledged that while there are uncertainties, the overall resource implications are favorable.
Evidence Quality and Robustness
The evidence base is primarily derived from the TRANSFORM trial, which is a robust Phase 3 study. While there are some concerns regarding generalizability and the maturity of OS data, the overall quality of evidence is strong, supporting the conclusions drawn by the committee.
Uncertainty, Sensitivity, and Broader Impacts
The committee recognized significant uncertainties related to the generalizability of the TRANSFORM trial results to Healthcare practice, particularly regarding long-term survival and the impact of subsequent treatments. While these uncertainties are acknowledged, they do not preclude the recommendation but indicate a need for cautious interpretation of the results.
