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BACKGROUND Larotrectinib and entrectinib are FDA-approved therapies for patients with non-small cell lung cancer (NSCLC) with neurotrophic receptor tyrosine kinase gene fusion (TRK fusion-positive) whose cancer has metastasized and progressed. Early evidence indicates that these targeted therapies may offer dramatic survival benefits versus traditional cytotoxic regimens, but it remains uncertain how larotrectinib and entrectinib compare with each other. OBJECTIVE To simulate and compare expected life-years and quality-adjusted life-years (QALYs) for both TRK inhibitors. METHODS We developed a partitioned survival model to project the long-term comparative effectiveness of larotrectinib versus entrectinib in second-line treatment of metastatic NSCLC. Larotrectinib survival data were derived from a 13-month follow-up of 12 patients with TRK fusion-positive NSCLC in the NCT02122913 (phase 1) and NCT02576431 (NAVIGATE) trials. Entrectinib survival data were derived from a 13-month follow-up of 10 patients with TRK fusion-positive NSCLC in the ALKA-372-001, STARTRK-1, and STARTRK-2 trials. For larotrectinib and entrectinib progression-free survival and overall survival (OS), in-trial survival was extrapolated using parametric curve fits. Exponential fits were selected for all survival models based on minimal Bayesian information criteria and clinical plausibility. Lifetime survival curves were used to estimate expected mean/median survival. QALYs were estimated by applying preprogression and postprogression health state utilities derived from the literature. RESULTS In the base case, treatment with larotrectinib and entrectinib resulted in 5.4 and 1.2 median preprogression life-years and 7.0 and 1.8 median total life-years, respectively. Mean preprogression life-years (QALYs) were 7.5 (5.0) and 1.9 (1.2), and mean total life-years (QALYs) were 9.2 (5.8) and 4.4 (2.4), respectively. CONCLUSIONS Among TRK inhibitors for metastatic NSCLC, larotrectinib is estimated to provide improved life-year and QALY outcomes versus entrectinib based on parametric extrapolations of in-trial survival data. Our analysis is limited by lack of NSCLC-specific data on entrectinib OS, the small samples of patients with NSCLC in the trials, and a cross-trial comparison. Future studies should re-evaluate the comparative effectiveness of larotrectinib versus entrectinib as more patients are treated and as long-term survival data mature. DISCLOSURES Funding for this study was contributed by Bayer Healthcare, which reviewed the manuscript drafts, and employees contributed to the manuscript as coauthors. Xia and Williamson are employees of Bayer Healthcare. Roth, Carlson, and Sullivan are consultants to Bayer Healthcare and retain rights to all final revisions to the manuscript. Carlson also reports fees from Adaptive Biotechnologies, unrelated to this work. Roth reports consulting fees from BMS, unrelated to this work.