Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The CROWN trial provides evidence that lorlatinib significantly increases progression-free survival compared to crizotinib, with a hazard ratio of 0.27. However, crizotinib is not typically used as a first-line treatment in the NHS, which raises concerns about the generalizability of these results. The indirect comparison with alectinib and brigatinib suggests potential benefits, but overall survival data remains immature and uncertain.
Cost effectiveness
The cost-effectiveness analysis indicates that lorlatinib is likely to be cost-effective within the acceptable ICER range, especially when considering the potential benefits in progression-free survival. However, uncertainties in the overall survival data and treatment sequences used in the CROWN trial introduce some caution.
Quality of life
HRQoL data from the CROWN trial indicates that lorlatinib has a positive impact on quality of life, particularly in managing CNS metastases. However, the committee noted that the utility values derived from the trial may not fully reflect the real-world experience, especially concerning adverse effects.
Supporting Domains
Safety and Adverse Effects
Lorlatinib has a manageable safety profile, with adverse effects that are generally mild to moderate and can be managed with supportive care. The committee acknowledged the potential for CNS-related adverse effects but noted that these are often manageable.
Comparator Selection
The primary comparator in the CROWN trial, crizotinib, is rarely used in the NHS as a first-line treatment, which limits the relevance of the trial results. The committee concluded that alectinib and brigatinib are more appropriate comparators, but the evidence from the trial does not directly address these treatments.
Patient Population and Subgroups
The trial population is broadly representative of the intended patient population with ALK-positive advanced NSCLC. However, the committee noted that there are uncertainties regarding the effectiveness in specific subgroups, particularly those with CNS metastases.
Care Pathway Integration
Lorlatinib can be integrated into existing treatment pathways with minor adjustments. The committee noted that healthcare professionals are already familiar with managing lorlatinib’s adverse effects, which facilitates its adoption.
Resource Use and Cost Implications
The budget impact of lorlatinib is manageable, especially considering the potential for cost savings through improved patient outcomes. The committee concluded that the resource implications are justifiable given the expected benefits.
Evidence Quality and Robustness
While the CROWN trial is a phase 3 RCT, there are concerns about the generalizability of the results due to the treatment sequences used. The evidence base is solid but has notable limitations that require caution in interpretation.
Uncertainty, Sensitivity, and Broader Impacts
There are significant uncertainties regarding overall survival and the applicability of trial results to NHS practice. The committee noted that these uncertainties could impact the decision-making process, particularly in terms of long-term outcomes.
