Low-grade glioma
A low-grade glioma is the most common form of brain tumors in children. It is a slow-growing tumor in the brain or spinal cord. If the tumor can be entirely removed by surgery, there is a good chance of cure. This may however not always be possible because of the location of the tumor. If so, additional treatment is necessary. This treatment can consist of chemotherapy and/or radiotherapy. The effect of these treatments, unfortunately, is limited. Moreover, side effects can cause damage to the brain. Therefore, new (targeted) drugs are needed that better inhibit tumor growth and reduce the risk of long-term side effects.
Targeted treatment: tovorafenib
Targeted treatment is treatment with drugs that go straight to their target: directly to the cancer cells. There, they stop the cancer cells from multiplying. Tovorafenib is an example of a targeted treatment. In tumor cells of among others children with low grade glioma, alterations may be present in specific genes. An example of such a gene is the BRAF gene. Alterations in the BRAF gene cause tumor cells to grow faster and survive better. Tovorafenib is a drug that can block the effect of alterations in a (B)RAF gene.
FIREFLY-1 trial
Tovorafenib has previously been studied in a small number of children with low-grade glioma. In this study, the side effects of the drug were mild and it appeared to inhibit tumor growth. With the FIREFLY-1 trial, researchers wanted to evaluate the safety and efficacy of tovorafenib in a larger group of children, adolescents and young adults. A total of 137 patients aged 1-24 years participated. All had low-grade glioma and alterations in the BRAF gene. They also had received one or more previous treatments.
Results
Treatment with tovorafenib caused the tumor to shrink or disappear completely in two-thirds of the patients. In an additional quarter of the patients, the tumor stopped growing. This effect was visible after three months on average and lasted for more than a year. 'Although there was no direct comparison with chemotherapy, this appears to be a much better response to therapy than we have seen so far for this group of tumors,' said pediatric oncologist dr. Jasper van der Lugt (Princess Máxima Center), who participated in the study.
All patients experienced one or more side effects. Examples of these side effects are changes in hair color, anemia, fatigue and skin rashes. But overall, the treatment was well tolerated. Seven percent of patients had to stop treatment because of side effects. The side effects of tovorafenib were less severe than those of chemotherapy and other drugs used in low-grade glioma.
Because of the good results, the researchers have set up an international phase 3 trial (LOGGIC/FIREFLY-2) in which the Máxima also participates. This trial will compare tovorafenib (DAY101) with standard chemotherapy in children and young adults with low-grade glioma and a BRAF alteration. In this study, treatment with tovorafenib is used as the first treatment.
The scientific publication can be found here: Kilburn LB, Khuong-Quang DA, Hansford JR, Landi D, van der Lugt J, et al. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med (2023).