Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG)

Abstract

Background: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors.

Methods: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D.

Results: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4).

Conclusions: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

Keywords: CNS tumors; entrectinib; pediatric; recommended phase 2 dose; solid tumors.

Fig. 1

CONSORT diagram. ^aFollowing implementation of protocol version 5 (October 25, 2018), enrollment in cohorts C and E was closed; cohort A was completed following dose-escalation recruitment. Enrollment continued in cohorts B (for patients with primary CNS tumors with gene fusions) and D (for patients with extracranial tumors with gene fusions). Following closure of cohort E, new patients that were unable to swallow capsules were enrolled in cohorts B and D, depending on their tumor type. Molecular testing was required, prior to enrollment in cohorts B or D.  ^bPatients in cohorts B, C, and D received entrectinib at the MTD (F1 formulation at 550 mg/m² or F06 formulation at 300 mg/m²), and patients in cohort E received entrectinib at 400 mg/m² (F1 formulation) mixed with soft foods. ^cPrimary CNS tumors, n = 5; extracranial solid tumors, n = 3; neuroblastoma, n = 1. The patient with neuroblastoma was not merged into cohorts B or D; they were followed up separately. Abbreviations: CNS, central nervous system; F1, F1 formulation; F06, F06 formulation; MTD, maximum tolerated dose; NTRK, neurotrophic tyrosine receptor kinase; ROS1, ROS proto-oncogene 1.

Fig. 2

Responses to entrectinib as assessed by BICR in patients with tumors harboring target gene fusions (n = 26). (A) Waterfall plot of BICR-assessed maximum percentage change in tumor size from baseline as measured by RECIST or RANO in patients with measurable target lesions. Plot includes 21 patients with both baseline and post-baseline measurements available for SLD or SPD. Five patients were excluded due to the presence of non-target lesions only (n = 3) or non-evaluable response (n = 2). Best overall confirmed responses per BICR assessment are also indicated; note that confirmed response does not align with best percentage improvement from baseline in SLD/SPD in 5 patients due to consideration of response in non-target lesions (n = 2), development of new lesions (n = 1), and requirement for confirmation of response after ≥28 days (n = 2; initial PR unconfirmed due to subsequent surgical resection [n = 1] or new lesion [n = 1]). (B) Swimmer plot of BICR-assessed best overall response from start of therapy to time of last therapy. Abbreviations: ALK, anaplastic lymphoma kinase; BICR, blinded independent central review; CNS, central nervous system; CR, complete response; HGG, high-grade glioma; IMT, inflammatory myofibroblastic tumors; NOS, not otherwise specified; NTRK, neurotrophic tyrosine receptor kinase; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; RECIST, Response Evaluation Criteria in Solid Tumors; ROS1, ROS proto-oncogene 1; SD, stable disease; SLD, sum of longest diameter; SPD, sum of products of diameters.

Fig. 3

Example MRI scans showing measurable and durable responses to entrectinib. (A) Primary CNS tumors. (B) An infant with a primary CNS tumor determined to be an anaplastic astrocytoma harboring an ETV6-NTRK3 fusion. Patient remains on treatment after 1 year. (C) Extracranial solid tumors. Per protocol, entrectinib was administered in 28-day cycles. Abbreviations: CNS, central nervous system; IMT, inflammatory myofibroblastic tumor; MRI, magnetic resonance imaging; NTRK, neurotrophic tyrosine receptor kinase; ROS1, ROS proto-oncogene 1.