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Larotrectinib enables children with sarcoma to proceed to surgery
WAILEA, Hawaii — Neoadjuvant larotrectinib enabled children with NTRK-fusion advanced sarcomas to proceed to surgery without increasing the risk for postsurgical complications or wound healing issues, according to phase 1/phase 2 study results presented at the Connective Tissue Oncology Society Annual Meeting.
NTRK fusions occur among patients with infantile fibrosarcoma and other pediatric sarcomas.
When limb preservation or function is threatened, systemic therapy may be used to cytoreduce locally advanced tumors prior to en bloc resection.
Larotrectinib (LOXO-101, Loxo Oncology) is a selective oral TRK inhibitor that has demonstrated significant activity among a variety of adult and pediatric NTRK-fusion cancers. A liquid formulation that masks the taste also is available for young children who are unable to swallow capsules.
In the phase 1 SCOUT trial — presented at this year’s ASCO Annual Meeting — Steven G. DuBois, MD, MS, director of experimental therapeutics at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and colleagues evaluated larotrectinib in 24 children aged 1 month to 21 years who had relapsed/refractory solid tumors or locally advanced infantile fibrosarcoma. Results showed that patients with TRK fusions appeared much more likely to experience tumor shrinkage.
“The objectives of the current report include to provide a detailed description of children with sarcoma who underwent resection after treatment with larotrectinib in the phase 1 study,” DuBois said during his presentation. “We evaluated pathologic responses following larotrectinib, and surgical outcomes, including margins and wound complications.”
Five patients (median age, 2 years; 40% female) underwent surgery following larotrectinib.
The first patient was a 2-year-old girl with infantile fibrosarcoma and ETV6-NTRK3 fusion. After progressing on two cycles of vincristine/actinomycin-D/cyclophosphamide, amputation was her only option. However, she achieved a partial response after four cycles of larotrectinib and proceeded to surgery. Pathology showed greater than 98% necrosis with R0 resection, and she had no functional deficit after surgery. She had been off larotrectinib for 8 months at the time of the analysis with no evidence of disease.
The second patient was a 5-month-old boy with progressive infantile fibrosarcoma and ETV6-NTRK3 fusion. After progression and inadequate response to chemotherapy, he received six cycles of larotrectinib, achieved partial response and proceeded to surgery. He also had R0 resection and no functional deficits and had been off therapy for 6 months with no evidence of disease.
The third patient was a 12-year-old boy with TPM3-NTRK1 spindle cell sarcoma, which lacks a standard therapy option. After nine cycles of larotrectinib this patient achieved partial response, underwent surgery, and achieved an uncomplicated R1 resection. His follow-up his ongoing.
The fourth patient was a 2-year-old boy with infantile fibrosarcoma and PDE4DIP-NTRK1 fusion who progressed after prior chemotherapy and surgery. He achieved an uncomplicated R1 resection following partial response to six cycles of larotrectinib.
The fifth patient was a 2-year-old girl with infantile fibrosarcoma and SQSTM1-NTRK1 fusion who previously underwent multiple lines of chemotherapy and two surgeries. She achieved a partial response after five cycles of larotrectinib.
“This promising early experience demonstrates that pediatric patients with TRK-fusion advanced sarcomas are able to proceed to surgical resection following presurgical larotrectinib, in settings where amputation and/or morbid surgery was the only other alternative,” DuBois said.
The phase 2 portion of the SCOUT trial is ongoing, and researchers also are considering a frontline trial. – by Alexandra Todak
Reference:
DuBois, et al. Abstract 032. Presented at: CTOS Annual Meeting; Nov. 8-11, 2017; Maui, Hawaii.
Disclosures: Loxo Oncology funded this study. DuBois and one other study author report a prior consultant role with Loxo Oncology. Three authors report employment with Loxo Oncology.