Abstract

2055 Background: BRAFV600E mutations, detected in 15-20% of pediatric low-grade gliomas (PLGGs), have emerged as a key therapeutic target for patients with unresectable, progressive, or recurrent PLGG. In a recent phase II clinical trial (NCT02684058), dabrafenib, a selective inhibitor targeting BRAFV600E, plus trametinib outperformed standard chemotherapy as first-line therapy, demonstrating significantly longer progression-free survival and improved safety in BRAFV600E-mutant PLGG. The aim of this study was to estimate the cost-effectiveness of dabrafenib+trametinib (Dab-Tram) versus standard chemotherapy as first-line therapy for patients with BRAFV600E-mutant PLGG. Methods: We constructed a microsimulation model, simulating a cohort of 10,000 patients with BRAFV600E PLGG. We populated the model using progression-free and overall survival estimates derived from the NCT02684058 trial, a hospital-based PLGG registry and treatment- and PLGG-related adverse events from published literature. The simulated cohort was assigned to either targeted therapy or chemotherapy as first-line therapy. Key parameters included treatment cost, dosage, inpatient and outpatient costs, and health-related quality of life. We assumed a lifetime duration of targeted therapy, a healthcare system perspective, lifetime horizon, and discount rate of 1.5%. Outcomes included life years, quality-adjusted life years (QALYs), lifetime costs (2022 CAD), and incremental cost-effectiveness ratios (ICERs).Sensitivity analysis included the use of alternative data sources, including those derived from independent assessment of NCT02684058 trial outcomes and real-world data from The Hospital for Sick Children (SickKids) in Toronto, Canada. Results: Modeled life years with Dab-Tram and chemotherapy were 34.91 and 32.68 years, respectively. Dab-Tram was associated with a 1.77 QALY increase at an incremental cost of $2,701,409 compared to standard chemotherapy. The resulting ICER was $1,526,265 per QALY gained. At a willingness-to-pay (WTP) threshold of $150,000 per QALY, a price reduction of approximately 80% is required to render it cost-effective. Scenario analysis varying effectiveness of targeted therapy using independent assessment of NCT02684058 trial outcomes and real-world data from SickKids demonstrated comparable clinical benefits and ICERs. Results were sensitive to changes in survival distributions. Conclusions: While clinical outcomes using Dab-Tram as first line therapy for BRAFV600E PLGG are promising, our model-based analysis demonstrates that at the present price, Dab-Tram is not cost-effective, and would require a considerable price reduction to enable equitable access and affordability. This work also provides an exemplar for economic evaluation of precision therapies based on emergent trial and real-world data for rare diseases.