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Clinical Trial
. 2025 May 2:220:115308.
doi: 10.1016/j.ejca.2025.115308. Epub 2025 Feb 22.

Efficacy and safety of entrectinib in children with extracranial solid or central nervous system (CNS) tumours harbouring NTRK or ROS1 fusions

Ami V Desai  1 , Aditi Bagchi  2 , Amy E Armstrong  3 , Cornelis M van Tilburg  4 , Ellen M Basu  5 , Giles W Robinson  6 , Huanmin Wang  7 , Michela Casanova  8 , Nicolas André  9 , Quentin Campbell-Hewson  10 , Yeming Wu  11 , Alison Cardenas  12 , Bo Ci  13 , Carolina Ryklansky  14 , Clare E Devlin  15 , Georgina Meneses-Lorente  16 , Jade Wulff  17 , Katherine E Hutchinson  18 , Amar Gajjar  19 , Elizabeth Fox  20
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Free article
Clinical Trial

Efficacy and safety of entrectinib in children with extracranial solid or central nervous system (CNS) tumours harbouring NTRK or ROS1 fusions

Ami V Desai et al. Eur J Cancer. .
Free article

Abstract

Background: Entrectinib, a central nervous system (CNS)-penetrant TRK/ROS1 inhibitor, has demonstrated clinical activity in children with NTRK1/2/3 or ROS1 fusion-positive extracranial solid and CNS tumours. We present integrated data of entrectinib in children with NTRK or ROS1 fusion-positive tumours from the STARTRK-NG, TAPISTRY, and STARTRK-2 trials.

Methods: Efficacy analyses were undertaken on TRK/ROS1 inhibitor-naïve patients aged <18 years with metastatic/locally advanced NTRK1/2/3 or ROS1 fusion-positive extracranial solid or CNS tumours who received ≥1 entrectinib dose and had ≥6 months of follow-up from enrolment. Tumour responses were confirmed by blinded independent central review (BICR) per RECIST v1.1/RANO criteria.

Primary endpoint: BICR-assessed confirmed objective response rate (cORR). Key secondary endpoints: duration of response (DoR); time to response (TtR); safety.

Results: As of 16 July 2023, out of 91 safety-evaluable patients, 64 (NTRK: n=44; ROS1: n=20) were efficacy evaluable. In the NTRK and ROS1 subgroups, respectively, median age was 4.0 years and 7.5 years; median survival follow-up was 24.2 months and 27.6 months. cORR was 72.7 % (NTRK, 95 % confidence interval [CI]: 57.2-85.0) and 65.0 % (ROS1, 95 % CI: 40.8-84.6). Median DoR was not reached (NTRK, 95 % CI: 25.4-not evaluable [NE]); ROS1, 95 % CI: 16.2-NE); median TtR was 1.9 months in both subgroups. The most frequently reported treatment-related adverse events included weight gain (35.2 %) and anaemia (31.9 %).

Conclusion: Integrated data from three trials confirm entrectinib induces rapid and durable responses in children with NTRK or ROS1 fusion-positive tumours. The increased duration of safety monitoring does not demonstrate new or cumulative toxicity. Registered clinical trials: STARTRK-NG: NCT02650401; TAPISTRY: NCT04589845; STARTRK-2: NCT02568267.

Keywords: CNS tumours; Entrectinib; NTRK fusions; Paediatric tumours; ROS1 fusions; ROS1 inhibitor; STARTRK-2; STARTRK-NG; TAPISTRY; TRK inhibitor.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.V.D.: Consulting or advisory role: GlaxoSmithKline, Recordati and Ymabs Therapeutics Inc; Travel, accommodations, expenses: Ymabs Therapeutics Inc; Stock and other ownership; Interests: Pfizer and Viatris; Research funding: Actuate Therapeutics, F. Hoffmann-La Roche, GlaxoSmithKline, Jubilant DraxImage, Lilly, Merck and YmAbs Therapeutics Inc, A.B.: None. A.E.A.: Consulting or advisory role: Alexion Pharmaceuticals; Springworks. C.M.vT.: Consulting or advisory role: Alexion, Bayer and Novartis. E.M.B.: None. G.W.R.: None. H.W.: None. M.C.: Consulting or advisory role: Roche, AstraZeneca, Bayer and Servier; Speaker’s Bureau: Bayer. N.A.: Consulting or advisory role: Alexion, Bayer, Roche and Partners Therapeutics; Research funding from Bristol Myers Squibb, drugs for a trial from Bristol Myers Squibb, Pfizer and Pierre Fabre; Travel: F. Hoffmann-La Roche, Alexion, Novartis; IDMC roles: Accord Healthcare. Q.C-H.: Current employment: The Newcastle upon Tyne Hospitals NHS Trust; Consulting or advisory role: Innovative Therapies for Children with Cancer (ITCC). Y.W.: None A.C.: Current employment: F. Hoffmann-La Roche/Genentech; Stocks/shares: F. Hoffmann-La Roche/Genentech. B.C.: Current employment: F. Hoffmann-La Roche/Genentech; Stocks/shares: F. Hoffmann-La Roche/Genentech. C.R.: Former employment: F. Hoffmann-La Roche/Genentech; Stocks/shares: Genentech. C.E.D.: Current employment: F. Hoffmann-La Roche; Stocks/shares: F. Hoffmann-La Roche/Genentech. G.M-L.: Current employment: F. Hoffmann-La Roche; Stocks/shares: F. Hoffmann-La Roche. J.W.: Current employment: F. Hoffmann-La Roche/Genentech; Stocks/shares: F. Hoffmann-La Roche. K.E.H.: Current employment: F. Hoffmann-La Roche/Genentech; Stocks/shares: F. Hoffmann-La Roche/Genentech. A.G.: Consulting or advisory role: F. Hoffmann-La Roche/Genentech, Gennao Bio and QED Therapeutics; Research Funding: Genentech and Kazia Therapeutics. E.F.: Current employment/Leadership: St Jude Children’s Research Hospital; Leadership: Children’s Oncology Group (grant funding)

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