Researchers at Children’s Hospital of Philadelphia (CHOP) and the Children’s Oncology Group (COG) found that larotrectinib, an oral drug that stops cancer-cell growth, was highly effective in pediatric patients with newly diagnosed infantile fibrosarcoma (IFS) or other solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation. The study, published in the Journal of Clinical Oncology, is the first COG trial to test precision medicine in a front-line setting across all different types of solid tumors based on a genetic biomarker rather than histology. It is poised to redefine the approach to treatment for newly diagnosed fibrosarcoma and other solid tumors with the NTRK gene fusion, potentially reducing or eliminating the need for these patients to receive chemotherapy.
“Precision medicine is transforming pediatric cancer care, offering tailored treatments that bring new hope for better outcomes and a brighter future for children and their families,” said Theodore W. Laetsch, MD, the lead study author and a pediatric oncologist at CHOP, who leads the hospital’s Developmental Therapeutics Program and Very Rare Malignant Tumors Program, as well as holding national leadership roles in each of these areas within COG.
IFS, a rare soft-tissue sarcoma, typically presents as a localized tumor. Although surgery often cures IFS, infants frequently present with fast-growing tumors that can’t be removed with surgery and require chemotherapy, which can pose serious harm to a young child’s developing organs and tissues.
Larotrectinib was approved in 2018 by the U.S. Food and Drug administration (FDA) for pediatric and adult patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to have severe side effects, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. Unlike traditional treatments directed at specific cancers based on their location in the body, larotrectinib targets the NTRK fusion present in the tumor, making it effective across various cancer types that share this mutation. Researchers have previously conducted front-line research of precision medicines for neuroblastoma and Ewings sarcoma, however, this is the first study to enroll patients with any cancer based on a specific genetic mutation.
In this study, researchers analyzed 33 patients between October 2019 and July 2022: 18 with IFS and 15 with other solid tumors. The patients, whose median age was 8, received larotrectinib twice daily in 28-day cycles for a predefined duration of treatment, ranging from 6 to 26 cycles depending on response to therapy and whether the tumor could be safely removed with surgery. The primary end point was the objective response rate (ORR) within six cycles in patients with IFS, which refers to the percentage of patients whose cancer shrinks or disappears completely after treatment based on medical tests. Secondary objectives included event-free survival (EFS) and overall survival (OS).
The ORR within six cycles was 94% among children with IFS and 60% among children with other solid tumors. Two patients, one with IFS and one with a different solid tumor, experienced disease progression while on the therapy and eventually died of their disease. The two-year EFS and OS among these groups were 82.2% and 93.8% for IFS and 80% and 93.3% for other solid tumors. Patients undergoing surgical resection of their tumor had prolonged EFS.
“This trial cements larotrectinib as the frontline therapy for patients with newly diagnosed fibrosarcoma and other solid tumors that also possess an NTRK gene fusion,” said Laetsch, who is also a member of the cellular therapy/chimeric antigen receptor (CAR) T-cell team at CHOP. “Our goal is always to present the safest and most effective treatment approach for our patients, which includes sparing them from the short and long-term complications of chemotherapy.”
The research was supported by an NCTN Operations Center Grant (U10CA180886), NCTN Statistics & Data Center Grant (U10CA180899), COG Biospecimen Bank Grant (U24CA196173), St Baldrick’s Foundation, Alex’s Lemonade Stand Foundation, and Bayer.
Laetsch is a consultant for Bayer, manufacturer of larotrectinib.
Laetsch et al. “Larotrectinib for Newly Diagnosed Infantile Fibrosarcoma and Other Pediatric NTRK Fusion–Positive Solid Tumors.” J Clin Oncol. Online December 9, 2024. DOI: 10.1200/JCO-24-01854.
