The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas

Abstract

BackgroundThe 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.MethodsA 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.ResultsA 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.ConclusionsChildren 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.

Gene rearrangements in consecutive series of pediatric inflammatory myofibroblastic tumors

“…Virtually all known rearrangements occurring in IMT are potentially actionable. Although there is a critical mass of clinical experience regarding the systemic treatment of ALK ‐ and ROS1 ‐rearranged IMTs, 26‐29 the use of NTRK ‐ and PDGFRb ‐targeted drugs is limited mainly to tumors of other types 7‐9 . Nevertheless, the high clinical value of comprehensive IMT testing for gene translocations is beyond doubt.…”

“…2,[4][5][6] The detection of these rearrangements is of high clinical value, as it ensures the reliability of morphological IMT diagnosis and provides grounds for therapeutic interventions. [7][8][9] Current diagnostic approaches are based on immunohistochemical (IHC) detection of activated kinases, FISH-based analysis of gene rearrangements, and identification of translocations by the next-generation sequencing (NGS).…”

Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer

“…A subset analysis of five children with locally advanced TRK fusion sarcomas treated with larotrectinib prior to surgical resection has also been reported [31]. All five patients (three with infantile fibrosarcoma and two with soft tissue sarcoma) achieved a partial response and underwent surgical resection after a median of six cycles.…”

New designs in early clinical drug development

“…Genomic alterations, such as chromosomal rearrangements involving neurotrophic receptor tyrosine kinase (NTRK), have been shown to drive tumourigenesis, due expression of a protein that causes a constitutively active kinase domain of TRK, leading to activation of the MAPK, PI3K and PLCc pathways which are critical for cell proliferation, differentiation, survival, and angiogenesis [42,43]. Several case reports and a phase I trial reported the activity of this molecule, with the first case published being of a soft tissue sarcoma [44][45][46][47][48][49]. Based on this promising clinical data, larotrectinib was the first molecule to receive breakthrough therapy designation for a tissueagnostic indication.…”