Abstract

TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers. Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes. We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers (P < 0.001) and lower tumor mutation burden (P < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8-13.2]. The best overall response rate achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI, 41-81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response. TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors.

Highlights

  • The NTRK genes (NTRK1/2/3) encode the family of TRK receptor tyrosine kinases (TrkA/B/C) that play a critical role in neuronal homeostasis during embryonic development [1, 2]

  • The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers (P < 0.001) and lower tumor mutation burden (P < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H)

  • Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases

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Summary

Introduction

The NTRK genes (NTRK1/2/3) encode the family of TRK receptor tyrosine kinases (TrkA/B/C) that play a critical role in neuronal homeostasis during embryonic development [1, 2]. TRK expression is primarily limited to the nervous system where these kinases are involved in pain sensing, memory, weight homeostasis, and proprioception [3, 4]. TRK is the target of recurrent fusion events across a wide variety of pediatric and adult cancers where they behave as classic oncogenic drivers [5,6,7]. TRK inhibitors have demonstrated dramatic and durable tumor-agnostic efficacy in TRK fusion–positive cancers [8,9,10]. For the first time in oncology therapy, TRK inhibitors laro-. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

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