@article{a9e49e28e8994052a94a4ca44d1c852f,
title = "The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas",
abstract = "Background: The highly selective oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib has demonstrated significant activity in adult and pediatric TRK fusion cancers. In the current study, the authors describe the clinical course of children with locally advanced TRK fusion sarcoma who were treated preoperatively with larotrectinib and underwent subsequent surgical resection. Methods: A total of 24 children were treated on a pediatric phase 1 trial of larotrectinib (ClinicalTrials.gov identifier NCT02637687). Five children who had a documented TRK fusion sarcoma and underwent surgical resection were included in the current analysis. Tumor response (Response Evaluation Criteria In Solid Tumors [RECIST] version 1.1) and surgical outcomes were collected prospectively. Results: A total of 5 patients (median age, 2 years; range, 0.4-12 years) had locally advanced infantile fibrosarcoma (3 patients) or soft-tissue sarcoma (2 patients). Four patients had disease that was refractory to standard therapy. All 5 patients achieved a partial response to larotrectinib by version 1.1 of RECIST and underwent surgical resection after a median of 6 cycles (range, 4-9 cycles) of treatment. Surgical resections were R0 (negative resection margins with no tumor at the inked resection margin) in 3 patients, R1 (microscopic residual tumor at the resection margin) in 1 patient, and R2 (macroscopic residual tumor at the resection margin) in 1 patient. Three patients achieved complete (2 patients) or near-complete (>98% treatment effect; 1 patient) pathologic responses. These patients remained in follow-up and were no longer receiving larotrectinib for a minimum of 7 to 15 months postoperatively. Two patients had viable tumor at the time of surgical resection and positive resection margins and continued to receive adjuvant larotrectinib. No patients experienced postoperative complications or wound healing issues. Conclusions: Children with locally advanced TRK fusion sarcomas may proceed to surgical resection after treatment with the selective TRK inhibitor larotrectinib, thereby sparing them the potentially significant morbidity noted with current approaches. These results support the evaluation of larotrectinib as presurgical therapy in children with newly diagnosed TRK fusion sarcomas.",
keywords = "infantile fibrosarcoma, larotrectinib, local control, neurotrophic receptor tyrosine kinase (NTRK), pediatric, sarcoma, surgery, tropomyosin receptor kinase (TRK) fusion.",
author = "DuBois, {Steven G.} and Laetsch, {Theodore W.} and Noah Federman and Turpin, {Brian K.} and Albert, {Catherine M.} and Ramamoorthy Nagasubramanian and Anderson, {Megan E.} and Davis, {Jessica L.} and Qamoos, {Hope E.} and Reynolds, {Mark E.} and Scott Cruickshank and Cox, {Michael C.} and Hawkins, {Douglas S.} and Leo Mascarenhas and Pappo, {Alberto S.}",
note = "Funding Information: Steven G. DuBois has received honorarium for advisory board participation and consulting and travel expenses from Loxo Oncology Inc and travel expenses from Roche/Genentech for work performed outside of the current study. Theodore Laetsch has acted as a paid member of the advisory board for Loxo Oncology Inc and as an unpaid member of the advisory board of and received travel reimbursement from Bayer for work performed as part of the current study and has acted as a member of the advisory boards for Novartis and Lilly and received a research grant to his institution from Pfizer for work performed outside of the current study. Noah Federman has received fees for consulting and advisory board roles from Loxo Oncology Inc and fees for advisory board roles and travel expenses from Bayer AG for work performed outside of the current study. Jessica Davis has participated in a pharmaceutical advisory board for Loxo Oncology Inc/Bayer Pharmaceuticals for work performed outside of the current study. Hope E. Qamoos is an employee of and stockholder in Loxo Oncology Inc. Mark E. Reynolds has received fees for Chemistry, Manufacturing, and Controls consulting from Loxo Oncology Inc for work performed outside of the current study and has a patent US15622544 pending. Scott Cruickshank has acted as a paid consultant and received fees for study design and statistical analysis from Loxo Oncology Inc for work performed as part of the current study. Michael Cox is an employee of and stockholder in Loxo Oncology Inc and a stockholder in Bayer AG. In addition, Dr. Cox has US Patent number 62/318,041 licensed to Loxo Oncology Inc. Douglas S. Hawkins has received travel expense reimbursement from Loxo Oncology Inc, Bayer, Celgene, and Bristol-Myers Squibb for work performed outside of the current study. Leo Mascarenhas reports that Loxo Oncology Inc is a sponsor of the Larotrectinib Phase 1 clinical trial, with all funds paid to the Children?s Hospital Los Angeles. The clinical trial was funded by Loxo Oncology Inc. Writing support was provided by Loxo Oncology Inc and Bayer AG to Jim Heighway of Cancer Communications. Additional support was provided by an Alex?s Lemonade Stand Foundation Center of Excellence Award (to Steven G. DuBois) and the National Institutes of Health National Center for Advancing Translational Sciences University of California at Los Angeles Clinical and Translational Science Institute grant UL1TR001881 (to Noah Federman). Funding Information: The clinical trial was funded by Loxo Oncology Inc. Writing support was provided by Loxo Oncology Inc and Bayer AG to Jim Heighway of Cancer Communications. Additional support was provided by an Alex{\textquoteright}s Lemonade Stand Foundation Center of Excellence Award (to Steven G. DuBois) and the National Institutes of Health National Center for Advancing Translational Sciences University of California at Los Angeles Clinical and Translational Science Institute grant UL1TR001881 (to Noah Federman). Publisher Copyright: {\textcopyright} 2018 American Cancer Society",
year = "2018",
month = nov,
day = "1",
doi = "10.1002/cncr.31701",
language = "English (US)",
volume = "124",
pages = "4241--4247",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "21",
}