Primary analysis of a Phase II trial of dabrafenib plus trametinib in BRAF V600–mutant pediatric low-grade glioma (pLGG).
In patients aged 1 to 17 years old with BRAF V600 pediatric low-grade glioma (pLGG) requiring first systemic treatment, Novartis, on 6th June 2022, announced that Tafinlar (dabrafenib) + Mekinist (trametinib) significantly improved efficacy compared to chemotherapy, the current standard-of-care for these patients.
Patients randomized to receive Tafinlar and Mekinist experienced a statistically significant overall response rate (ORR) of 47% compared to 11% for those randomized to receive chemotherapy. A new liquid formulation of Tafinlar + Mekinist that can be easier to administer than chemotherapy was used in this trial. Additional findings from the Phase II/III trial revealed that median progression-free survival (PFS) with Tafinlar + Mekinist was 20.1 months compared to 7.4 months with chemotherapy after a median follow-up of 18.9 months. Furthermore, tumors decreased or stayed stable in 86% of Tafinlar + Mekinist patients (n=73), compared to 46% of chemotherapy patients (n=37). After a year of follow-up, nearly all Tafinlar + Mekinist patients (89%) experienced a reduction in tumor size, compared to 70% of chemotherapy patients. Tafinlar + Mekinist was found to be superior to chemotherapy at all time points in a quality-of-life study.
The combination had a safety profile that was generally consistent with prior studies' findings. Patients in the Tafinlar + Mekinist arm reported fewer grade 3 or higher adverse events (AEs; 47% vs. 94%) and fewer AE-related discontinuations (4% vs. 18%) than those in the chemotherapy arm (n=33).
Low-grade glioma (grade I/II) accounts for most pediatric cases, with BRAF V600E mutations present in approximately 15% to 20% of cases. Surgery is central to treatment, but it is not always possible if the tumor has invaded a particular part of the brain. Patients with BRAF mutant disease tend to be less responsive to standard chemotherapy.
Low-Grade Glioma is itself challenging when we look at the patient pool and the targeted population. In children harboring BRAFV600E mutations with progressive disease following surgery, the overall response rate (ORR) reached a "striking'' 47% with dabrafenib (Tafinlar) plus trametinib (Mekinist) versus just 11% with carboplatin plus vincristine.
BRAF and IDH mutations are mainly associated with low-grade glioma accounting for the maximum number of mutations in this indication. Since this combination of Tafinlar + Mekinist is already approved for non-small cell lung cancer and BRAF-Positive anaplastic thyroid cancer, and with the encouraging results of this trial, it will be interesting to note the journey in the pediatric segment.
Novartis is not alone in the Low-grade glioma space and will have to lock horns with Day One Biopharmaceuticals, AnHeart Therapeutics, and Daiichi Sankyo, who are also coming up with their effective treatment options.
Companies- Novartis, Day One Biopharm, AnHeart Therapeutics, Daiichi Sankyo, and others