Efficacy and safety of entrectinib in children with extracranial solid or central nervous system (CNS) tumours harbouring NTRK or ROS1 fusions
Ami V. Desai, Aditi Bagchi, Amy E. Armstrong, Cornelis M. van Tilburg, Ellen M. Basu, Giles Robinson, Huanmin Wang, Michela Casanova, Nicolás André, Quentin Campbell-Hewson, Yeming Wu, Alison K. Cardenas, Bo Ci, Carolina Ryklansky, Clare Devlin, Georgina Meneses‐Lorente, Jade Wulff, Katherine E. Hutchinson, Amar Gajjar, Elizabeth Fox
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.