Entrectinib Produces Response in Children with Refractory CNS Tumors

Entrectinib is a central nervous system (CNS)-penetrant oral inhibitor of tropomyosin receptor kinase (TRK), ROS1, and anaplastic lymphoma kinase (ALK) tyrosine kinases. Research presented at the 2019 ASCO Annual Meeting found that first-line use of entrectinib in children with refractory CNS and solid tumors harboring NTRK1/2/3ROS1, or ALK fusions “produced striking, rapid, and durable responses.”

The open-label, dose-escalation, phase I/II STARTRK-NG study included patients ≤20 years with recurrent/refractory solid tumors. Researchers determined a recommended dose in each patient and enrolled disease-specific expansion cohorts of CNS and solid tumors harboring target aberrations in NTRK1/2/3ROS1, or ALK and neuroblastoma (NBL), regardless of mutation spectrum.

Between May 2016 and October 2018, 29 patients aged 4.9 months to 20 years (median age = 7 years) were enrolled and 28 were evaluated for response. Entrectinib was well tolerated, according to the researchers, and responses occurred in 12 of the evaluable patients.

Dose-limiting toxicities that were observed included elevated creatinine, dysgeusia, fatigue, and pulmonary edema. The recommended dose was 550 mg/m2 daily. All responses occurred at doses ≥400 mg/m2.

Among patients with CNS tumors (n=6), all high-grade with gene fusions, one achieved a complete response (CR; ETV6-NTRK3), three achieved a partial response (PR; TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2), one achieved an unconfirmed PR (GOPC-ROS1), and one had not been evaluated (KANK1-NTRK2).

Among patients with extracranial solid tumors (n=8), six of which had a fusion, one achieved a CR (DCTN1-ALK) and five achieved a PR (TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3).

Among patients with NBL (n=15), one achieved a CR (ALK F1174L).

Median duration of therapy was 85 days (range = 6-592 days) for all patients, 56 days (range = 6-338 days) for non-responders, and 281 days (range = 56-592 days) for responders. Median time to response was 57 days (range = 30-58 days).

 No responses were observed in tumors without aberrations in the target kinases.

“These results support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3ROS1, and ALK fusions, especially in high-grade CNS neoplasms,” the researchers concluded.

 Reference

Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1B trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors. Abstract #10009. Presented at the 2019 ASCO Annual Meeting, Chicago, IL, June 2, 2019.