What is the effect of entrectinib on glioma?

Entrectinib (Entrectinib) targeting oncogenic fusion genes in pediatric high-grade glioma (pHGG) has emerged as a very promising treatment. Although clinical studies are ongoing, to date, there are no reports on the treatment of disseminated fusion-positive pHGG in the cerebrospinal fluid (CSF). Furthermore, there is a lack of clinically important information on the use in combination with other treatment modalities such as intrathecal therapy, radiotherapy, and other targeted agents. Entrectinib is a selective pan-TRK inhibitor that has shown significant efficacy in NTRK fusion tumors, including primary central nervous system tumors and central nervous system metastases.

The STARTRK-NG trial included four patients with pHGG who received entrectinib. All patients had radiation reactions, including one complete response. To date, only a few reports in the literature describe primary NTRK fusion CNS tumors treated with larotrectinib or entrectinib. An adult patient with a BCAN:NTRK1 fusion glial neuronal tumor experienced disease progression after 11 months of entrectinib treatment. Two reports describe patients with low-grade glioma (LGG), one showing a greater than 50% reduction in NACC2:NTRK fusion tumor volume and the other showing a complete response to ETV6:NTRK3 fusion tumors treated with larotrectinib.

In addition, in two casesETV6:NTRK3 fusion-positive pHGG, larotrectinib was administered. One patient experienced more than 70% tumor volume reduction and one episode of disease progression. In a pooled analysis of the STARTRK-2, STARTRK-1 and ALKA-371-001 trials, the overall median progression-free survival in patients with CNS disease was 7.7 months, with most observed responses occurring within the first or second treatment cycle. This is consistent with the observed response to leptomeningeal spread of tumors after four weeks of entrectinib treatment. The progression-free survival observed with entrectinib treatment in patients with gliosarcoma was 5 months, which is comparable to what has been observed in various trials. In contrast, in patients with IHG, tumor progression was significantly slowed but not completely blocked, and treatment with entrectinib was still ongoing 16 months after starting treatment.

In terms of patient treatment, entrectinib was well tolerated, with the most common adverse events including dysgeusia, fatigue, constipation, diarrhea, dizziness, peripheral edema, weight gain, and anemia. In the case study, neither patient had entrectinib-related side effects.

Enrectinib demonstrates efficacy of repeated daily oral administration in preclinical modelCNS penetration ability. In the study, the CSF penetrance of entrectinib in patients could be demonstrated for the first time. Entrectinib can be detected in the CSF of gliosarcoma patients, with concentrations increasing over time. The entrectinib concentrations detected were in the same range or even slightly higher than those reported in animal models. Therefore, entrectinib appears to have potential in the treatment of high-grade gliomas with NTRK fusions, particularly when leptomeningeal dissemination occurs.