The Potential Long-Term Comparative Effectiveness of Larotrectinib Vs. Entrectinib for Treatment of Metastatic Fusion-Positive Cancers in Children and Young Adults

OBJECTIVES:

Larotrectinib and entrectinib are approved for pediatric and adult patients with fusion-positive advanced solid tumors. Previous comparative effectiveness studies have demonstrated promising results for larotrectinib compared to entrectinib in adult patients with metastatic tropomyosin receptor kinase fusion cancers. A recent analysis of entrectinib in children and young adults (age<22) with fusion-positive tumors was conducted but was not a comparative study. We compared expected life-years (LYs) and quality-adjusted life-years (QALYs) for pediatric and young adult patients with metastatic solid tumor cancers eligible to receive larotrectinib or entrectinib.

METHODS:

We developed a partitioned survival model to project long-term comparative effectiveness of larotrectinib vs. entrectinib. Larotrectinib survival data, assessed by independent review committee, were derived from an updated July 2022 analysis of 92 pediatric and young adult patients from the larotrectinib clinical trials program (NCT02122913, NCT02637687, and NCT02576431). Survival inputs for 26 patients treated with entrectinib were informed from NCT02650401. Progression free (PFS) and overall survival (OS) were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal) fit to the available data. Exponential fits were used based on goodness-of-fit and clinical plausibility. QALYs were estimated by adjusting the time spent in the pre and post progression health states by utilities derived from publicly available literature. Model uncertainty was evaluated using one-way and probabilistic sensitivity analyses.

RESULTS:

The larotrectinib model estimated 13.67 LYs (95% Credible Interval [CrI]: 9.03, 18.95) and 5.66 QALYs (95% CrI: 1.92, 14.07). The entrectinib model estimated 7.96 LYs (95% CrI: 4.48, 17.72) and 3.52 QALYs (95% CrI: 1.40, 10.84). Compared to entrectinib, larotrectinib produced additional gains of 5.71 LYs and 2.13 QALYs.

CONCLUSIONS:

In pediatric and young adult patients with metastatic fusion-positive tumors, larotrectinib may produce substantial life expectancy and quality-adjusted life-year gains compared to entrectinib. Additional data with longer follow-up times will further inform this comparison.