Targeted treatment with larotrectinib for newly diagnosed high-grade glioma with an NRTK gene fusion

High-grade gliomas (HGG) are fast-growing brain tumors that invade deep into healthy tissue and are difficult to remove completely. They originate from the brain’s support cells, known as glial cells, and can impair important functions such as movement, speech, or breathing. If the tumor is located in areas such as the brainstem or thalamus, it is referred to as a diffuse intrapontine glioma (DIPG), which is particularly difficult to treat due to its location.

The standard treatment usually consists of a combination of surgery, radiation therapy, and chemotherapy. If possible, the tumor is surgically removed, followed by radiation therapy to slow its growth and chemotherapy to target any remaining tumor cells. In cases involving specific genetic alterations, such as NTRK gene fusions or BRAF mutations, targeted therapies can be used to improve the chances of successful treatment. One such drug is the study drug larotrectinib, which has already been approved for tumors with NTRK gene fusions. It specifically inhibits tropomyosin receptor kinases (TRK), a group of signaling proteins that play a key role in cellular communication and tumor growth, and demonstrated promising results in its approval trial for tumors with NTRK gene fusions. The success of the treatment is assessed based on the tumor’s response: Complete Response (CR) means that the tumor has completely disappeared; Continued Complete Response (CCR) confirms that this state persists over an extended period; Partial Response (PR) describes a significant but incomplete shrinkage of the tumor; and Stable Disease (SD) means that the tumor is neither growing nor shrinking.

The goal of the study is to test the drug larotrectinib for efficacy and safety in high-grade gliomas. The drug is already approved for tumors with NTRK gene fusions. The study is now intended to provide additional data specifically for gliomas. To this end, patients will be divided into two groups, depending on whether surgery has already been performed or is not possible (Group 1) or whether surgical removal of the tumor is planned (Group 2). In Group 1, patients will initially receive the drug larotrectinib for two cycles, each lasting 28 days. The drug is taken as a capsule twice daily. If the tumor disappears completely (CR/CCR), treatment will continue for at least 12 to 24 additional cycles. Otherwise, a combination of chemotherapy or radiation therapy may follow. In Group 2, larotrectinib is administered twice daily for 3–5 days prior to a scheduled surgery. After the tumor is surgically removed, the concentration of the drug in the tumor tissue is also measured. Further follow-up as part of the study will continue for up to 5 years. All patients will receive the study drug.

Children up to and including 21 years of age who have a high-grade glioma with an NTRK gene fusion are eligible to participate in the study. Patients must not have received any prior drug treatment for their condition, other than corticosteroid therapy.