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AACR 2022: Is Response to Larotrectinib Influenced by NTRK Gene Fusion Variability?

By: Vanessa A. Carter, BS
Posted: Thursday, April 21, 2022

Marc Ladanyi MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues evaluated whether the fusion exon junction organization of NTRK fusions may impact a patient’s response to the TRK inhibitor larotrectinib. Presented during the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract CT545), the results of this study identified 36 different fusion variants and 20 different NTRK gene fusions.

“Despite the variability of the fusion structure, larotrectinib was equally efficacious,” concluded the investigators. “The large number of potential different fusion partners and involvement of various breakpoints highlight the need for validated and appropriate testing methodologies that are agnostic of 5' partners and breakpoints.”

The study authors focused on 80 patients with 14 different nonprimary, central nervous system cancers harboring NTRK fusions who were treated with larotrectinib. Participants were analyzed from three clinical trials (ClinicalTrials.gov identifiers NCT02122913, NCT02576431, and NCT02637687). Local molecular testing was performed to determine NTRK gene fusion data.

The median patient age was 47, and the objective response rate was 82.5%. The most common NTRK aberration was a fusion of NTRK3 (56%), followed by NTRK1 (40%) and NTRK2 (4%); specifically, the most frequent fusions were ETV6-NTRK3 (49%), TPM3-NTRK1 (13%), and LMNA-NTRK1 (9%). Of note, there were 12, 5, and 3 different fusion partners of NTRK1, NTRK3, and NTRK2, respectively.

Intrachromosomal rearrangement events were the most prevalent fusion (60%), responsible for eight, two, and two events related to NTRK1, NTRK2, and NTRK3, respectively. A total of 35 different 5'/3' gene breakpoint combinations were located at the NTRK1 exons 8 through 13, NTRK2 exons 15 and 16, and NTRK3 exons 14 and 15. Furthermore, ETV6-NTRK3 fusion points existed at exon 14 for 10 of 11 thyroid carcinomas as well as 3 of 13 salivary gland tumors.

Disclosure: For full disclosures of the study authors, visit abstractsonline.com.


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