TRK Fusions are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations

Ezra Y Rosen, Debra A Goldman, Jaclyn F Hechtman, Ryma Benayed, Alison M Schram, Emiliano Cocco, Sophie Shifman, Yixiao Gong, Ritika Kundra, James P Solomon, Alberto Bardelli, Maurizio Scaltriti, Alexander Drilon, Alexia Iasonos, Barry S Taylor, David M Hyman

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.

RESULTS: 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 TMB (p<0.001), with the exception of colorectal cancer where TRK fusions co-occur 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. PFS on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months (95% CI: 4.8-13.2). The best ORR achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI: 41-81). Among 12 patients treated with checkpoint inhibitors, an MSI-H colorectal patient had the only observed response.

CONCLUSIONS: 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.

Original languageEnglish
JournalClin. Cancer Res.
DOIs
Publication statusE-pub ahead of print - Dec 23 2019

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