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

Eur J Cancer. 2025 May 2:220:115308. doi: 10.1016/j.ejca.2025.115308. Epub 2025 Feb 22.

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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Adolescent
  • Benzamides / adverse effects
  • Benzamides / therapeutic use
  • Central Nervous System Neoplasms* / drug therapy
  • Central Nervous System Neoplasms* / genetics
  • Central Nervous System Neoplasms* / pathology
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Indazoles / adverse effects
  • Indazoles / therapeutic use
  • Infant
  • Male
  • Membrane Glycoproteins
  • Oncogene Proteins, Fusion* / genetics
  • Protein Kinase Inhibitors* / adverse effects
  • Protein Kinase Inhibitors* / therapeutic use
  • Protein-Tyrosine Kinases* / antagonists & inhibitors
  • Protein-Tyrosine Kinases* / genetics
  • Proto-Oncogene Proteins* / antagonists & inhibitors
  • Proto-Oncogene Proteins* / genetics
  • Receptor, trkA* / antagonists & inhibitors
  • Receptor, trkA* / genetics
  • Receptor, trkB / genetics
  • Receptor, trkC* / antagonists & inhibitors
  • Receptor, trkC* / genetics
  • Treatment Outcome

Substances

  • Benzamides
  • entrectinib
  • Indazoles
  • NTRK1 protein, human
  • NTRK3 protein, human
  • Oncogene Proteins, Fusion
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Receptor, trkA
  • Receptor, trkB
  • Receptor, trkC
  • ROS1 protein, human
  • tropomyosin-related kinase-B, human
  • Membrane Glycoproteins

Associated data

  • ClinicalTrials.gov/NCT02568267
  • ClinicalTrials.gov/NCT02650401
  • ClinicalTrials.gov/NCT04589845