Abstract LB-B18: The Potential Long-Term Comparative Effectiveness of Larotrectinib vs. Entrectinib for Second-Line Treatment of NTRK Fusion-Positive Metastatic Non-Small Cell Lung Cancer
Authors: Roth Joshua A , Carlson Josh J , Williamson Todd , Sullivan Sean D 
Published: March 2020

Abstract
Background: Larotrectinib and Entrectinib are FDA-approved for patients with non-small cell lung cancer (NSCLC) that has neurotrophic receptor tyrosine kinase gene fusion (NTRK+), are metastatic, and whose cancer has progressed. Early evidence indicates that these targeted therapies may offer potentially dramatic survival benefits vs. traditional cytotoxic regimens, but it remains uncertain how Larotrectinib and Entrectinib compare to each other. The objective of this study was to simulate and compare expected life years and Quality-Adjusted Life Years (QALYs) for both NTRK-targeted therapies. Methods: We developed a partitioned survival model to project long-term comparative effectiveness of Larotrectinib vs. Entrectinib in second-line treatment of metastatic NSCLC. Larotrectinib survival data were derived from 13-month follow-up of 12 NTRK+ NSCLC patients in the NCT02122913 (Phase 1) and NCT02576431 (NAVIGATE) trials. Entrectinib survival data were derived from 13-month follow-up of 54 NTRK+ patients (10 NTRK+ NSCLC patients) in the ALKA-372-001, STARTRK-1, and STARTRK-2 trials. For larotrectinib progression free (PFS) and overall survival (OS) and entrectinib OS, in-trial survival was extrapolated using parametric curve fits (Weibull, Exponential, Log-Logistic, Gamma). For entrectinib PFS, an exponential model was fit to the median PFS estimate for the 10 NTRK+ NSCLC patients. Exponential fits were selected for all base case survival models based on minimal Bayesian Information Criteria (BIC), clinical plausibility, and visual inspection. Lifetime survival curves were used to estimate expected mean and median progression-free and overall survival duration. QALYs were estimated by applying pre-progression and post-progression health state utilities and Grade 3/4 adverse event disutilities derived from literature. Results:In the base case, treatment with larotrectinib and entrectinib resulted in 5.4 and 1.3 median pre-progression life years and 7.0 and 1.9 median total life years, respectively. Mean pre-progression life years (QALYs) were 6.5 (4.3) and 1.8 (1.2) and mean total life years (QALYs) were 7.5 (4.8) and 2.5 (1.5), respectively. Discussion Among NTRK fusion protein-targeted therapies for metastatic NSCLC, larotrectinib is estimated to provide improved life year and QALY outcomes vs. 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 sample size of NSCLC patients in source trials, and a naïve direct (cross-trial) comparison. Future studies should re-evaluate the comparative effectiveness of larotrectinib vs. entrectinib as greater numbers of patients are treated and as long-term survival data mature.
Citation Format: Joshua A Roth, Josh J Carlson, Todd Williamson, Sean D Sullivan. The Potential Long-Term Comparative Effectiveness of Larotrectinib vs. Entrectinib for Second-Line Treatment of NTRK Fusion-Positive Metastatic Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B18. doi:10.1158/1535-7163.TARG-19-LB-B18