Investigating the natural history and prognostic nature of NTRK gene fusions in solid tumors.

Limin Zhu,David S Hong,Vijaykumar Holla,Brian Hobbs,Jason Roszik

doi:10.1007/s10637-021-01157-8

Abstract

Several TRK inhibitors have demonstrated clinical efficacy in patients with solid tumors harboring NTRK gene fusions. However, the natural history and prognostic implications of NTRK fusions in solid tumors remain unknown. A cohort of 77 MD Anderson Cancer Center patients (MDACC) with NTRK gene fusions was identified and retrospectively compared to a second cohort from the Cancer Genome Atlas (TCGA) database. Due to paucity of events in early stage cancers and lack of TCGA data in rare tumors, 25 randomly selected MDACC patients were matched to 122 TCGA patients without NTRK gene fusion. Next we assessed the associations between NTRK gene fusion and overall (OS) and progression-free survivals (PFS). Among the 77 MDACC patients with NTRK gene fusions, 18 NTRK fusion partners were identified. There were insufficient OS events for analysis in the matched cohort. PFS was not significantly different (p = 0.49) between the NTRK-fusion positive MDACC patients (median PFS 786weeks, 95% CI 317-NE) and the NTRK-fusion negative TCGA patients (median PFS NE). The adjusted hazard ratio comparing TCGA patients to MDACC patients was HR = 0.72 (95% CI: 0.23-2.33), which trended towards a reduced rate of progression or death experienced by TCGA patients. This study did not identify statistically significant associations between NTRK fusion and PFS. Nonsignificant trends estimated increases in the risk of progression or death events for patients with NTRK fusions when compared to matched controls. Our findings help illuminate the influence of NTRK fusions on the natural history of a variety of solid tumors.

Highlights

Neurotrophic tyrosine receptor kinases (NTRK) 1, 2, and 3 are three distinct genes that encode the tropomyosin receptor kinase (TRK) proteins TRK A, B and C respectively [1]
Our study identified multiple novel NTRK fusions that have not been previously reported in literature
Our analysis of progression-free survival included 25 NTRK fusion-positive patients from 4 different tumor types and 21 of them had thyroid cancer which is known to be a solid tumor with relatively high frequency of NTRK fusions

Summary

Introduction

Neurotrophic tyrosine receptor kinases (NTRK) 1, 2, and 3 are three distinct genes that encode the tropomyosin receptor kinase (TRK) proteins TRK A, B and C respectively [1]. Larotrectinib, a highly selective and potent pan-TRK inhibitor, has showed durable antitumor efficacy in children and adults with solid tumors harboring NTRK gene fusions [8]. Despite the robust clinical responses to TRK inhibitors, the natural history and prognostic implications of NTRK fusions in solid tumors is poorly understood, mostly due to the rarity of such mutations. Several TRK inhibitors have demonstrated clinical efficacy in patients with solid tumors harboring NTRK gene fusions. Due to paucity of events in early stage cancers and lack of TCGA data in rare tumors, 25 randomly selected MDACC patients were matched to 122 TCGA patients without NTRK gene fusion. Nonsignificant trends estimated increases in the risk of progression or death events for patients with NTRK fusions when compared to matched controls. Our findings help illuminate the influence of NTRK fusions on the natural history of a variety of solid tumors

Methods

Results

Conclusion