Primary Risk Drivers
Below is a snapshot of domains that materially influence the MARA Rating.
Clinical effectiveness
The evidence from the RAMP-201 cohort indicates a confirmed objective response rate (ORR) of 44% in 57 adults with KRAS-mutated recurrent low-grade serous ovarian cancer. However, the lack of a head-to-head comparison against standard of care (SOC) limits the ability to conclude superiority. The FDA’s accelerated approval based on ORR and duration of response (DOR) suggests some efficacy, but the absence of comparative data against SOC results in a B++ rating.
Cost effectiveness
There is no published cost-utility analysis or incremental cost-effectiveness ratio (ICER) for the combination of avutometinib and defactinib. The only cost information available is the wholesale acquisition cost (WAC) of $48,500, which does not provide sufficient evidence for cost-effectiveness. Therefore, a C rating is warranted.
Quality of life
No HRQoL data or validated measurement instruments were reported for the RAMP-201 cohort. Although the RAMP-301 trial plans to collect HRQoL data using validated tools, the absence of any reported HRQoL outcomes in the current evidence leads to a C rating.
Supporting Domains
Safety and Adverse Effects
The FDA label reports a range of adverse reactions, with the most common being nausea (74%), diarrhea (68%), and fatigue (72%). Serious adverse reactions occurred in 32% of patients, with a fatality rate of 3.6%. Despite these concerns, the overall safety profile is manageable, leading to a rating of A+.
Comparator Selection
The RAMP-201 trial was a single-arm study without a direct comparator to SOC, which limits the ability to assess comparative efficacy. The upcoming RAMP-301 trial is designed to compare the combination against SOC, but currently, the lack of head-to-head data results in a B++ rating.
Patient Population and Subgroups
The trial population is well-defined, including 57 adults with measurable KRAS-mutated recurrent LGSOC. However, the representativeness may be limited due to specific exclusion criteria. Overall, the population is adequately characterized, leading to an A rating.
Care Pathway Integration
The treatment can be integrated into existing pathways with minor adjustments, as it involves oral administration of both agents. The monitoring requirements are clearly defined, indicating that integration into clinical practice is feasible with manageable changes.
Resource Use and Cost Implications
The WAC of $48,500 is known, but there are no detailed analyses of the broader resource implications or budget impact. The lack of comprehensive cost data leads to a B rating, indicating potential concerns about affordability.
Evidence Quality and Robustness
The evidence is primarily derived from a single-arm phase 2 trial with no head-to-head comparisons. While the trial design is acceptable, the reliance on a single study and the pending confirmatory trial introduce some uncertainty, resulting in a B++ rating.
Uncertainty, Sensitivity, and Broader Impacts
There are notable uncertainties regarding the long-term clinical benefit and cost-effectiveness due to the lack of comparative data and pending confirmatory trials. While the trial design includes plans for interim analysis, the overall uncertainty leads to a B+ rating.
