2019 ASCO: Entrectinib in Children and Adolescents With Recurrent or Refractory Solid or Central Nervous System Tumors
A phase I/IB study evaluating the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors, including central nervous system (CNS) tumors, has found that the agent produced responses in children with tumors harboring target aberrations in NTRK1/2/3, ROS1, or ALK gene fusions, as well as ALK-mutated neuroblastoma. Entrectinib is a central nervous system–penetrant oral selective inhibitor of TrkA/B/C, ROS1, and ALK tyrosine kinases. Responses were not seen in tumors lacking aberrations in target kinases.
These results support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3, ROS1, and ALK gene fusions, especially in high-grade central nervous system cancers. The study by Robinson et al will be presented during the 2019 ASCO Annual Meeting (Abstract 10009).
Study Methodology
Patients ≤ 20 years old with recurrent or refractory solid tumors were eligible to participate in the trial. After the researchers determined the recommended dose of entrectinib in all of the participants, disease-specific expansion cohorts of CNS and other solid tumors harboring target aberrations in NTRK1/2/3, ROS1, or ALK, and neuroblastoma, regardless of mutation spectrum, were enrolled.
Response rates, assessed by the investigators, were classified as complete response, partial response, stable disease, or progressive disease, using Response Assessment in Neuro-Oncology for CNS tumors, Response Evaluation Criteria in Solid Tumors, and Curie scoring for neuroblastoma.
Between May 2016 and October 2018, 29 patients aged 4.9 months to 20 years were enrolled in the study, and 28 were evaluated for response.
Study Results
Entrectinib was well tolerated by the study participants. Dose-limiting toxicities included elevated creatinine, dysgeusia, fatigue, and pulmonary edema. The recommended dose was 550 mg/m2 daily. All responses occurred at doses ≥ 400 mg/m2.
In CNS tumors (n = 6), all high-grade with gene fusions, 1 patient achieved a complete response (ETV6-NTRK3); 3 patients achieved a partial response (TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2); 1 patient achieved an unconfirmed partial response (GOPC-ROS1), and 1 patient has yet to be evaluated (KANK1-NTRK2).
In extracranial solid tumors (n = 8), 6 patients had a fusion; 1 achieved a complete response (DCTN1-ALK) and 5 achieved a partial response (TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3,KIF5B-ALK, ETV6-NTRK3). In the patients with neuroblastoma (n = 15), 1 achieved a complete response (ALK F1174L). The median duration of therapy was 85 days (6–592 days) for all patients; 56 days (6–338 days) for nonresponders; and 281 days (56–592 days) for responders. The median time to response was 57 days (30–58 days).
“Entrectinib produced striking, rapid, and durable responses in all children with refractory CNS and solid tumors harboring NTRK1/2/3, ROS1, or ALK fusions (11 out of 11), as well as in an ALK-mutated neuroblastoma. No responses were seen in tumors lacking aberrations in target kinases. These results support the continued evaluation of entrectinib as a targeted therapeutic in solid tumors with NTRK1/2/3, ROS1, and ALK fusions, especially in high-grade CNS neoplasms,” concluded the study authors.
“Our results show that children with life-threatening cancers can benefit greatly even after other conventional therapies have not worked—we’ve seen some rapid and durable responses, which is very gratifying,” said study author Giles W. Robinson, MD, a pediatric neuro-oncologist at St. Jude Children's Research Hospital. “These early findings suggest that this therapy holds great promise for those whose tumors have these specific gene fusions.”
Disclosure: Funding for this study was provided by F. Hoffman-La Roche Ltd. For full disclosures of the study authors, visit coi.asco.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
