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.

person Giles W. Robinson St. Jude Children's Research Hospital, Memphis, TN info_outline Giles W. Robinson, Amar J. Gajjar, Karen Marie Gauvain, Ellen M. Basu, Margaret E Macy, Luke Devon Maese, Amit J. Sabnis, Jennifer Haunani Foster, Suzanne Shusterman, Janet Yoon, Brian D. Weiss, Mohamed Abdelbaki, Mufiza Farid-Kapadia, Georgina Meneses-Lorente, Alison Cardenas, Katherine Hutchinson, Guillaume Bergthold, Edna Chow Maneval, Elizabeth Fox, Ami Vijay Desai

Authors person Giles W. Robinson St. Jude Children's Research Hospital, Memphis, TN info_outline Giles W. Robinson, Amar J. Gajjar, Karen Marie Gauvain, Ellen M. Basu, Margaret E Macy, Luke Devon Maese, Amit J. Sabnis, Jennifer Haunani Foster, Suzanne Shusterman, Janet Yoon, Brian D. Weiss, Mohamed Abdelbaki, Mufiza Farid-Kapadia, Georgina Meneses-Lorente, Alison Cardenas, Katherine Hutchinson, Guillaume Bergthold, Edna Chow Maneval, Elizabeth Fox, Ami Vijay Desai Organizations St. Jude Children's Research Hospital, Memphis, TN, Washington University School of Medicine, St. Louis, MO, Memorial Sloan Kettering Cancer Center, New York, NY, Children's Hospital Colorado, Aurora, CO, University of Utah/Huntsman Cancer Institute, Primary Children's Hospital, Salt Lake City, UT, University of California San Francisco, Benioff Children’s Hospital, San Francisco, CA, Texas Children’s Hospital, Houston, TX, Dana Farber Cancer Institute, Boston Children’s Cancer and Blood Disorders Center, Boston, MA, Rady Children's Hospital, San Diego, CA, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, Nationwide Children's Hospital, Columbus, OH, F. Hoffmann-La Roche Limited, Mississauga, ON, Canada, Roche Products Limited, Welwyn Garden City, United Kingdom, Genentech, South San Francisco, CA, F. Hoffmann-La Roche, Basel, Switzerland, Ignyta, Inc., San Diego, CA, Children's Hospital of Philadelphia, Philadelphia, PA, University of Chicago Medical Center, Chicago, IL Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Entrectinib is a CNS-penetrant oral inhibitor of TrkA/B/C, ROS1 and ALK tyrosine kinases. We report the efficacy of entrectinib in children with recurrent/refractory solid or CNS tumors. Methods: Patients ≤ 20y old with recurrent/refractory solid tumors were eligible. After determination of the recommended dose in all-comers, disease-specific expansion cohorts of CNS and solid tumors harboring target aberrations in NTRK1/2/3 , ROS1 or ALK , and neuroblastoma (NBL), regardless of mutation spectrum, were enrolled. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using RANO for CNS tumors, RECIST for solid tumors, and Curie score for NBL. Results: Between May 2016 and October 2018, 29 patients aged 4.9m–20y (median 7y) were enrolled and 28 were evaluated for response. Entrectinib was well tolerated. Dose limiting toxicities were elevated creatinine, dysgeusia, fatigue and pulmonary edema. The recommended dose was 550 mg/m 2 daily. All responses occurred at doses ≥ 400 mg/m 2 . In CNS tumors (n = 6), all high-grade with gene fusions: 1 achieved a CR ( ETV6-NTRK3 ); 3 achieved a PR ( TPR-NTRK1, EEF1G-ROS1, EML1-NTRK2 ); 1 achieved an unconfirmed PR ( GOPC-ROS1 ); and 1 has yet to be evaluated ( KANK1-NTRK2 ). In extracranial solid tumors (n = 8), 6 had a fusion of whom 1 achieved a CR ( DCTN1-ALK ) and 5 achieved a PR ( TFG1-ROS1, EML4-NTRK3, ETV6-NTRK3, KIF5B-ALK, ETV6-NTRK3 ). In NBL (n = 15): 1 achieved a CR ( ALK F1174L). Median duration of therapy was 85d (6–592d) for all patients; 56d (6–338d) for non-responders; and 281d (56–592d) for responders. Median time to response was 57d (30–58d). Conclusions: 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 NBL. 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. Clinical trial information: NCT02650401