NEW YORK – Bayer's TRK inhibitor Vitrakvi (larotrectinib) could replace chemotherapy as a first-line treatment for pediatric patients with NTRK fusion-positive solid tumors, a new study from the Children's Oncology Group suggests.
NTRK gene fusions are found among a range of pediatric cancer types, including gliomas, thyroid cancers, congenital mesoblastic nephromas, and infantile fibrosarcoma (IFS), where ETV::NTRK3 fusions are present in about 85 percent of patients, and in NTRK-rearranged spindle cell neoplasms. IFS is typically treated first with surgery and chemotherapy or radiation therapy.
The US Food and Drug Administration approved Vitrakvi in 2018 for the treatment of adult and pediatric patients with NTRK fusion-positive solid tumors. Patients also had to have metastatic disease, and they became eligible for this tissue-agnostic indication only after they became refractory to other treatments or ran out of treatment options.
In the Phase II ADVL1823 study, researchers from the Children's Oncology Group, a clinical trials group that is part of the National Cancer Institute's National Clinical Trials Network, explored Vitrakvi as a first-line treatment for pediatric patients whose tumors harbored NTRK gene fusions, regardless of tumor tissue type. As they reported in the Journal of Clinical Oncology on Monday, the researchers found Vitrakvi was highly active in patients with newly diagnosed NTRK fusion-positive solid tumors, indicating a biomarker-based approach could guide treatment and potentially reduce the need for 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," first author Theodore Laetsch, a pediatric oncologist at CHOP, who leads the hospital's developmental therapeutics and very rare malignant tumors programs, said in a statement.
In ADVL1823, the researchers enrolled 33 previously untreated patients, 18 of whom had IFS and 15 of whom had another solid tumor, most commonly NTRK-rearranged spindle cell tumors. Patients' gene fusions were identified locally via either FISH, RT-PCR, or next-generation sequencing analysis. The patients' median age in the study was 8 years old.
Researchers had a third, exploratory cohort where they had hoped to study Vitrakvi in NTRK fusion-positive relapsed or refractory leukemia, but they didn't enroll any patients into this arm.
In the trial, the patients were given Vitrakvi orally twice a day in 28-day cycles. The number of treatment cycles varied based on each patient's response to treatment and whether their tumor could be surgically resected but ranged from six to 26 cycles.
The objective response rate within six cycles, the primary endpoint of the Phase II trial, was 94 percent among IFS patients and 60 percent among patients with other solid tumors.
In addition, the two-year event-free survival was 82.2 percent in IFS and 80 percent in other solid tumors, while the two-year overall survival was 93.8 percent and 93.3 percent, respectively. All patients with IFS exhibited a response after further treatment, the researchers noted, and patients who underwent surgical resection of their tumors had longer event-free survival.
Two patients, one with IFS and one with another solid tumor, experienced disease progression while on therapy and died.
Eleven patients experienced a treatment-related grade 3 or higher adverse event, the most common of which was neutropenia. Four adverse events were dose-limiting but no patient discontinued treatment due to an adverse event, indicating to the researchers that the therapy was largely well tolerated.
Due to the drug's efficacy and toxicity profile, the researchers believe Vitrakvi should be considered as a frontline treatment option for children with IFS and related NTRK-rearranged spindle cell tumors, noting that local control with surgical resection remains important in IFS treatment.
"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 consultant for Vitrakvi sponsor Bayer. "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."