Entrectinib Active in Pediatric Gene-Fusion Tumors

The multikinase inhibitor entrectinib demonstrated safety and activity in children and young adults with advanced, previously treated central nervous system tumors, according to a phase I study presented at the 2018 ASCO Annual Meeting.<br /> &nbsp;

Ami V. Desai, MD

The multikinase inhibitor entrectinib demonstrated safety and activity in children and young adults with advanced, previously treated central nervous system (CNS) tumors, according to a phase I study presented at the 2018 ASCO Annual Meeting.

All 3 patients with gene fusions responded to treatment with entrectinib. 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),” Ami Vijay Desai, MD, 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.

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.

Investigators enrolled patients ages 2-21 with recurrent or refractory extracranial solid tumors and primary CNS tumors, with or withoutNTRK 1/2/3,ROS1, orALKgene 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.

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 (IMT), and 1 each with infantile fibrosarcoma (IFS), salivary glad adenocarcinoma, and synovial sarcoma. Three patients had tumors with target gene fusions: both patients with IMT (DCTNI-ALKandTFG-ROS1) and the patient with IFS (EML4-NTRK3).

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.

Clinical activity in the patients with gene fusion-associated tumors consisted of a complete response in the patient withDCTN1-ALKIMT (ongoing at 10 months), a partial response in the patient withTFG-ROS1IMT (ongoing at 8 months), and a partial response in the patient withEML4-NTRK3IFS (ongoing at 2.5 months). Four patients remain on treatment, including 1 with neuroblastoma.

“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.

Reference:

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).