Nature medicine 2023 Nov 17
The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial.
Abstract
BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .
Related Questions
In pediatric patients with low-grade gliomas showing prolonged response or stable disease on tovorafenib, how would you adjust the duration of therapy?
This is a one-million-dollar question. As far as I know, the design of FIREFLY-2 includes a fixed duration of treatment, and this is also the case for ACSN1833 (selumetinib trial). It will be important to look at the PFS of the patients who discontinued tovorafenib and compare with the results of ch...
Based on the FIREFLY-1 data, would you consider using tovorafenib monotherapy front-line in pediatric patients who have low grade gliomas that are only amenable to subtotal resection or are unresectable?
Not yet. I think it is important to wait for the results of FIREFLY-2 and also ACNS1831/ACNS1833. We have to keep in mind that the combination of trametinib and dabrafenib is already FDA-approved as frontline treatment for paediatric patients with BRAF V600 mutated LGG. This approval was based on th...
What was the rationale behind using RANO-HGG criteria instead of RAPNO criteria for the primary endpoint in the FIREFLY-1 trial for pLGG?
I think this was a mistake, but I understand that this was requested by the FDA. We all know that MEK and BRAF inhibitors change the pattern of enhancement within days/weeks after the beginning of the treatment. As RANO-HGG is essentially based on the assessment of enhancing measurable and nonmeasur...
Would you consider combining tovorafenib and trametinib as dual therapy?
A phase 1/2 study of tovorafenib and the MEK inhibitor selumetinib is planned through the Developmental Therapeutics Committee of the Children's Oncology Group for low-grade gliomas that have failed appropriate prior MAPK blocking therapy and other patients with BRAF/RAF1, RAS, and NF driven maligna...
How has the recent FDA approval of tovorafenib impacted your treatment decisions for pediatric patients with relapsed/refractory low-grade glioma?
With the FDA approval, and given the tolerability of therapy and the pediatric friendly once weekly dosing and formulations, I will prescribe tovorafenib regularly for my patients with relapsed refractory low grade glioma. I do think it will become a standard choice in this setting. That said, given...