Outcomes for Patients With Central Nervous System Tumors Harboring NTRK Gene Fusions
According to an international retrospective cohort study, among patients with central nervous system (CNS) tumors and confirmed neurotrophic tyrosine receptor kinase (NTRK) fusions, pediatric patients and those with low-grade glioma had better overall survival (OS) when compared to adult patients with glioma and high-grade glioma. Additionally, tyrosine receptor kinase (TRK) inhibitors may result in favorable overall response and progression-free survival (PFS) when compared to previous therapies.
For pediatric patients, NTRK gene fusions have been identified in up to 5/3% of patients with high-grade gliomas and 2.5% of low-grade glioma — rates that are higher than those in all solid tumors and adult primary CNS tumors. Food and Drug Association (FDA)-approved therapies for NTRK fusion-positive tumors include larotrectinib, a selective pan-TRK inhibitor, and entrectinib, a multikinase inhibitor.
In this international, multicenter, retrospective cohort study included 119 patients with CNS tumors and NTRK fusions, with confirmed TRK fusion, diagnosed between 2000 and 2021. The median follow-up duration for the entire cohort was 38.5 months. The median age at the time of diagnosis was 4.5 years, with 45.3% of the patients were infants of <3 years of age. The median age of the adult cohort (n = 17) was 50 years. A majority of patients (57.1%) had high-grade glioma, with 27.7% having low-grade glioma. Among the pediatric patients, high-grade glioma was predominantly found among those patients <3 years of age. Within the overall population, 24.4% had a NTRK1 fusion, 50.4% had a NTRK2, and 25.2% had a NTRK3, with no specific NTRK gene found to be associated with any specific histology.
Regarding initial treatment, 40 patients underwent surgery without further treatment and 72 patients received a “nontargeted therapy,” such as chemotherapy, radiation therapy or a systemic therapy other than TRK inhibitors. There were 7 patients who received TRK inhibitors upfront. Including all lines of therapy, a total of 51 patients received TRK inhibitor therapy. The initial TRK inhibitor was larotrectinib for 39 patients and entrectinib for 3 patients (not specified, n = 7; others, n = 2).
Among 63 evaluable (of 99 total) lines of nontargeted therapies, 38.1% resulted in an objective response. Of 35 evaluable nontargeted regimens among patients with pediatric high-grade glioma, the objective response rate was 45.2%. Among 33 separate instances of treatment with TRK inhibitors, 42.4% resulted in an objective response. Of 22 evaluable separate treatment instances among patients with high-grade glioma, the objective response rate of 45.5% overall and 90.0% among pediatric patients. There were 16 evaluable (of 23 total) lines of larotrectinib administered to pediatrics patients, with an objective response rate of 68.8% overall and 100% among those patients with high-grade glioma.
At the last follow-up, 74% of all patients were still alive. The median OS was 185.5 months overall and the median PFS was 25.5 months overall. Pediatric patients had a better OS compared to adult patients (185.5 months vs 24.8 months; P < .0001), but the median PFS was not significantly different (25.8 months vs 11.1 months; P = .22). Patients with low-grade glioma had a better OS (not reached) compared to those with low-grade glioma (99.5 months) and embryonal tumors (38.5 months; P = .0012). This difference was also significant among the pediatric cohort (P = .021). Pediatric patients with high-grade glioma had a better outcome compared to adult patients with high-grade glioma. NTRK gene fusion type was not associated with a difference in OS.
Study authors concluded, “young age and low-grade histology are associated with improved outcomes” and that “TRK [inhibitor] therapy seems to improve tumor control in a subset of patients, most notable for pediatric [high-grade glioma].” They went on to note, “Additional prospective study and clinical trials are needed to improve management of patients with CNS tumors and NTRK fusion.”
Source:
Lamoureux A, Fisher MJ, Lemelle L, et al. Clinical characteristics and outcomes of central nervous system tumors harboring NTRK gene fusions. Clin Canc Research. February 3, 2025. doi:10.1158/1078-0432.CCR-24-0581
