All 3 patients with targeted gene fusions responded to the multikinase inhibitor entrectinib, according to a phase I study in children and young adults with advanced, previously treated central nervous system tumors.
Ami Vijay Desai, MD
All 3 patients with targeted gene fusions responded to the multikinase inhibitor entrectinib, according to a phase I study in children and young adults with advanced, previously treated central nervous system (CNS) tumors. Ami Vijay Desai, MD, presented these findings during the 2018 ASCO Annual Meeting.
Clinical activity in the patients with gene fusion-associated tumors consisted of a complete response in the patient with DCTN1-ALK inflammatory myofibroblastic tumors (ongoing at 10 months), a partial response in the patient with TFG-ROS1 inflammatory myofibroblastic tumors (ongoing at 8 months), and a partial response in the patient with EML4-NTRK3 infantile fibrosarcoma (ongoing at 2.5 months). Four patients remain on treatment, including 1 with neuroblastoma.
Toxicity associated with the drug was similar to what was observed in prior trials involving adults with CNS tumors.
“The recommended phase II dose of entrectinib in children, adolescents, and young adults with solid tumors is 550 mg daily (versus 600 mg in adults),” Desai, a pediatric hematology/oncology specialist at the University of Chicago, and coinvestigators concluded. “Activity was observed in patients with fusion-positive tumors, including ALK, ROS1, and NTRK gene fusions.”
Entrectinib is a selective inhibitor of the tyrosine kinases TRK A/B/C, ROS1, and ALK. The drug crosses the blood-brain barrier, and studies demonstrated clinical activity in adults with primary brain tumors and secondary CNS metastases. Studies involving preclinical models showed activity against neuroblastoma associated with TRKB overexpression, the authors noted.
Investigators enrolled patients ages 2-21 with recurrent or refractory extracranial solid tumors and primary CNS tumors, with or without NTRK 1/2/3, ROS1, or ALK gene fusions. Desai and colleagues reported findings for 15 patients evaluable for dose-limiting toxicity (DLT). The patients were treated at entrectinib doses of 250 mg to 750 mg.
In previous phase I/II studies involving adults, treatment-related adverse events (TRAEs) were primarily grade 1/2 and reversible with dose modification of entrectinib. In 1 trial, 2 dose-limiting toxicities occurred at 800 mg daily: 1 case each of grade 3 cognitive disturbance and fatigue, both of which resolved with drug interruption.
The trials demonstrated clinical efficacy of entrectinib in patients with gene-fusion tumors, and most responses occurred rapidly and proved to be durable, the authors continued.
The trial in pediatric patients had a primary endpoint of determining the recommended phase II dose of entrectinib for pediatric patients, including young adults. Secondary endpoints included safety, antitumor activity, and intracranial tumor response.
Three patients had received no prior treatment; 7 had received more than 4 regimens. All but 4 patients had neuroblastoma. The remaining patients, including 1 not evaluable for DLT, consisted of 2 with inflammatory myofibroblastic tumors, and 1 each with infantile fibrosarcoma, salivary glad adenocarcinoma, and synovial sarcoma.
Three DLTs occurred during dose escalation: 1 case of grade 2 creatinine elevation for more than 7 days at the 550-mg dose, which did not occur again when the dose cohort was increased from 3 to 6 patients; 1 case each of grade 2 dysgeusia with fatigue and grade 3 pulmonary edema at the 750-mg dose.
The most common TRAEs were elevated creatinine, elevated aspartate aminotransferase, and nausea. In general, the overall drug exposure and safety/toxicity profiles were similar to those observed in trials of adult patients, the authors noted. No patient discontinued treatment because of adverse events.
“Entrectinib continues to be investigated in expansion cohorts of patients with extracranial solid tumors or primary CNS tumors harboring somatic gene fusions, as well as patients with neuroblastoma,” noted Desai during her presentation.
Desai AV, Brodeur GM, Foster J, et al. Phase I study of entrectinib (RXDX-101), a TRK, ROS1, and ALK inhibitor, in children, adolescents, and young adults with recurrent or refractory solid tumors. J Clin Oncol. 2018;36(suppl;abstr 10536).