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. 2025 Feb 3;31(3):561-572.
doi: 10.1158/1078-0432.CCR-24-0581.

Clinical Characteristics and Outcomes of Central Nervous System Tumors Harboring NTRK Gene Fusions

Audrey-Anne Lamoureux  1 , Michael J Fisher  2 , Lauriane Lemelle  3 , Elke Pfaff  4   5   6 , Pouneh Amir-Yazdani  1 , Christof Kramm  7 , Bram De Wilde  8 , Bernarda Kazanowska  9 , Caroline Hutter  10   11 , Stefan M Pfister  4   5   6 , Dominik Sturm  4   5   6 , David T W Jones  4   5   6 , Daniel Orbach  3 , Gaëlle Pierron  3 , Scott Raskin  12 , Alexander Drilon  13 , Eli L Diamond  13 , Guilherme Harada  13 , Michal Zapotocky  14 , Josef Zamecnik  15 , Lenka Krskova  15 , Benjamin Ellezam  1 , Alexander G Weil  1 , Dominic Venne  1 , Marc Barritault  16 , Pierre Leblond  17 , Hallie Coltin  18 , Rawan Hammad  19   20 , Uri Tabori  19 , Cynthia Hawkins  19 , Jordan R Hansford  21   22   23   24   25   26   27 , Deborah Meyran  24   25   26   27 , Craig Erker  28 , Kathryn McFadden  28 , Mariko Sato  29 , Nicholas G Gottardo  30   31   32 , Hetal Dholaria  30   31   32 , Dorte Schou Nørøxe  33 , Hiroaki Goto  34 , David S Ziegler  35   36   37 , Frank Y Lin  38 , Donald Williams Parsons  38 , Holly Lindsay  38 , Tai-Tong Wong  39 , Yen-Lin Liu  39 , Kuo-Sheng Wu  39 , Andrea T Franson  40 , Eugene Hwang  41 , Ana Aguilar-Bonilla  42 , Sylvia Cheng  43 , Chantel Cacciotti  44 , Maura Massimino  45 , Elisabetta Schiavello  45 , Paul Wood  46   47   48 , Lindsey M Hoffman  49 , Andréa Cappellano  50 , Alvaro Lassaletta  51 , An Van Damme  52 , Anna Llort  53 , Nicolas U Gerber  54 , Mariella Spalato Ceruso  55 , Anne E Bendel  56 , Maggie Skrypek  56 , Dima Hamideh  57 , Naureen Mushtaq  58 , Andrew Walter  59 , Nada Jabado  60 , Aysha Alsahlawi  60 , Jean-Pierre Farmer  60 , Christina Coleman  60 , Sabine Mueller  61 , Claire Mazewski  62 , Dolly Aguilera  62 , Nathan J Robison  63 , Katrina O'Halloran  63 , Samuel Abbou  64 , Pablo Berlanga  64 , Birgit Geoerger  64 , Ingrid Øra  65   66 , Christopher L Moertel  67 , Evangelia D Razis  68 , Anastasia Vernadou  68 , François Ducray  16 , Charlotte Bronnimann  69 , Romuald Seizeur  70 , Matthew Clarke  71 , Adam C Resnick  72 , Mélanie Alves  1 , Chris Jones  71 , François Doz  3   73 , Theodore W Laetsch  2 , Sébastien Perreault  1
Affiliations

Clinical Characteristics and Outcomes of Central Nervous System Tumors Harboring NTRK Gene Fusions

Audrey-Anne Lamoureux et al. Clin Cancer Res. .

Abstract

Purpose: Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients.

Experimental design: We conducted an international retrospective cohort study of patients with TRK fusion-driven central nervous system tumors.

Results: A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment.

Conclusions: Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.

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Conflict of interest statement

M.J. Fisher reports grants and other support from Alexion/AstraZeneca, other support from SpringWorks and Day 1, and grants from Array Biopharma/Pfizer and Exelixis outside the submitted work. L. Lemelle reports grants from Bayer Inc. and SFCE—Imagine for Margo during the conduct of the study. C. Kramm reports grants, personal fees, and nonfinancial support from Merck and Deutsche Kinderkrebsstiftung; personal fees and nonfinancial support from Rover/Blueprint and Novartis; personal fees from Novogene and Boehringer Ingelheim; and nonfinancial support from Oncoscience during the conduct of the study. S.M. Pfister reports nonfinancial support from PMC and Epignostix GmbH and personal fees from BioSkryb outside the submitted work; in addition, S.M. Pfister shares a patent with D.T.W. Jones, David Capper, Andreas von Deimling, Martin Sill, and Volker Hovestadt for DKFZ, University Hospital Heidelberg DNAMethylation based method for classifying tumor species (European Patent 16 710700.2) issued and has unpaid membership in GPOH, SIOP, DGNN, and DKG. D.T.W. Jones reports personal fees from Day 1 Biopharmaceuticals and other support from Heidelberg Epignostix GmbH outside the submitted work. D. Orbach reports grants from Bayer Inc. and SFCE—Imagine for Margo during the conduct of the study. G. Pierron reports grants from Bayer Inc. and SFCE—Imagine for Margo charity during the conduct of the study. A. Drilon reports personal fees from 14ner/Elevation Oncology, Amgen, Anheart Therapeutics, AbbVie, ArcherDX, AstraZeneca, Bayer, Beigene, BergenBio, Blueprint Medicines, Boundless Bio, Bristol Myers Squibb, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Innocare, Janssen, Loxo/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Regeneron, Repare RX, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem, and Zymeworks and other support from mBrace, Treeline, Boehringer Ingelheim, Merck, and Puma during the conduct of the study as well as other support from Foundation Medicine, Teva, Taiho, GlaxoSmithKline, and PharmaMar and personal fees from Answers in CME, Applied Pharmaceutical Science, Inc., AXIS, Clinical Care Options, Doc Congress, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MedTalks, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education Resources, Projects in Knowledge, Resources, Remedica Ltd., Research to Practice, RV More, Springer Healthcare, Targeted Oncology, TouchIME, WebMD, Wolters Kluwer, and UpToDate outside the submitted work; in addition, A. Drilon has a patent for Selpercatinib-Osimertinib (US 18/041617, pending) pending. E.L. Diamond reports personal fees from Opna Bio, nonfinancial support from Pfizer Inc., and personal fees from Day 1 Biopharmaceuticals and SpringWorks Therapeutics outside the submitted work. G. Harada reports personal fees from Bristol Myers Squibb, MSD, Lilly, Takeda, Pfizer, AstraZeneca, Daiichi, Sanofi, Novartis, and J&J outside the submitted work. M. Zapotocky reports personal fees from AstraZeneca outside the submitted work. A.G. Weil reports personal fees from Monteris Medical Inc. and Synergia SA outside the submitted work. H. Coltin reports personal fees from Alexion Pharma Canada Corp. outside the submitted work. R. Hammad reports other support from Vertex outside the submitted work. J.R. Hansford reports personal fees from Servier International, Alexion Pharmaceuticals, and Bayer Pharmaceuticals outside the submitted work. N.G. Gottardo reports other support from Bayer outside the submitted work. H. Goto reports personal fees from Bayer during the conduct of the study. D.S. Ziegler reports personal fees from Bayer during the conduct of the study as well as grants and personal fees from Accendatech and personal fees from Novartis, Day 1, FivePhusion, Amgen, Alexion, Norgine, and Medison Pharma outside the submitted work. H. Lindsay reports personal fees from Day 1 Bio outside the submitted work. Y.-L. Liu reports grants and personal fees from Bayer; grants from Turning Point Therapeutics Inc., a subsidiary of Bristol Myers Squibb Co.; and personal fees from AstraZeneca, Roche, Novartis, JW Diagnostics, and CancerFree Biotech outside the submitted work. A.T. Franson reports personal fees from Bayer outside the submitted work. E. Hwang reports personal fees from Day 1 Therapeutics outside the submitted work. S. Cheng reports other support from Bayer outside the submitted work. L.M. Hoffman reports personal fees from Day 1 Biopharmaceuticals and Bayer outside the submitted work. A. Lassaletta reports other support from Alexion and Servier and personal fees from Pfizer outside the submitted work. N.J. Robison reports grants from Pfizer outside the submitted work. S. Abbou reports other support from Fore Pharmaceutical and Lilly outside the submitted work; in addition, S. Abbou has a patent for EP3613436B1 issued. P. Berlanga reports other support from Bayer and EUSA Pharma/Recordati outside the submitted work. C.L. Moertel reports other support from OX2 Therapeutics and personal fees from SpringWorks Therapeutics and Alexion Pharmaceuticals outside the submitted work; in addition, C.L. Moertel has a patent for Patent No. US 9364505 B2 issued and a patent for International Patent No. WO 2020/150149 A1 issued. E.D. Razis reports personal fees from Bayer, AstraZeneca, Servier, Novartis, Gilead, Pfizer, Genesis Pharm, and Bristol Myers Squibb outside the submitted work. F. Doz reports personal fees from Roche, Ipsen, Servier, Novartis Pharma S.A.S.; grants from Onxeo Valerio; and nonfinancial support from Synth-Innove outside the submitted work. T.W. Laetsch reports grants and personal fees from Bayer and Jazz Pharmaceuticals; personal fees from GSK, AI Therapeutics, Advanced Microbubbles, and ITM Oncologics; and grants from Pfizer outside the submitted work. S. Perreault reports grants from Roche and Bayer during the conduct of the study as well as grants and personal fees from Alexion, grants from Novartis and SpringWorks Therapeutics, and personal fees from Bayer and Esai outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
NTRK fusion partners. CIRCOS schematic representation of NTRK genes and fusion partners.
Figure 2.
Figure 2.
OS outcome. A, OS of the entire cohort. B, OS of adult compared with pediatric patients (P < 0.0001). C, OS according to histology (P = 0.012). D, OS according to NTRK fusion type (P = 0.180). E, OS according to CDKN2A/B alteration (P = 0.053). F, OS in pediatric patients with HGG who received or did not receive radiotherapy at one point during their treatment (P = 0.695). P value from the log-rank test.
Figure 3.
Figure 3.
PFS outcome. A, PFS of the entire cohort. B, PFS of adult compared with pediatric patients (P = 0.219). C, PFS according to histology (P = 0.303). D, PFS according to NTRK fusion type for the pediatric cohort (P = 0.042). E, PFS according to CDKN2A/B alteration (P = 0.066). F, PFS according to CDKN2A/B alteration for patients with HGG (P = 0.452). P value from the log-rank test.
Figure 4.
Figure 4.
Kaplan–Meier plot of PFS on TRKis or larotrectinib specifically and TTP on the previous line of therapy. A, The 31 patients for whom the GMI was calculated (regardless of histology)—PFS on TRKi therapy and their TTP on the previous line of therapy. B, The 23 patients with HGG for whom the GMI was calculated—PFS on TRKi therapy and their TTP on the previous line of therapy. C, The 23 patients treated with larotrectinib for whom the GMI was calculated (regardless of histology)—PFS on larotrectinib therapy and their TTP on the previous line of therapy. D, The 17 patients with HGG treated with larotrectinib for whom the GMI was calculated—PFS on larotrectinib and their TTP on the previous line of therapy.
See this image and copyright information in PMC

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