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 .

Fig. 1. FIREFLY-1 patient disposition/CONSORT diagram.

This report presents efficacy data from the evaluable population (enrolled patients who received at least one dose of tovorafenib and met the prespecified efficacy analysis criteria per each radiological assessment method according to the IRC) in arm 1 (registrational) and the safety data from arms 1 and 2 (safety analysis set) as of a 5 June 2023 datacut. Patients were enrolled in arm 2 (extension) after arm 1 had fully accrued and closed for enrollment. ^aNot radiologically confirmed. ^bOnly patients with measurable disease at baseline per independent review were included.

Fig. 2. Maximal change in tumor size for evaluable patients.

Per RANO-HGG (a), RAPNO (b) and RANO-LGG (c) criteria. Two patients are not shown in the waterfall plots. One patient died due to PD (not tovorafenib related) before the first tumor assessment, and one patient with missing T1 gadolinium-enhanced imaging at baseline was deemed not evaluable. The dashed lines indicate the range of growth/shrinkage of target lesions to be considered as one of the requirements for PD, SD, MR, PR or CR. BRAFi, BRAF inhibitor.

Fig. 3. Swimlane plot of TTR and DOT.

Per RANO-HGG (a) and RAPNO (b) criteria. In patients with response, symbols indicate the start of response (MR, PR or CR). If initial responses improved with continued treatment (from MR to confirmed PR or from PR to confirmed CR), both the timepoint of the initial response and the timepoint that the response initially improved are marked accordingly. BRAFi, BRAF inhibitor.

Extended Data Fig. 1. Tumor kinetics.

Fig. 1a shows tumor kinetics in patients who progressed while on therapy per RANO-HGG but continued to receive tovorafenib and who had at least one assessment from a scheduled visit post-PD. Fig. 1b,c show tumor kinetics in patients with best response of progressive disease according to RAPNO and RANO-LGG criteria, respectively. In some patients, who continued therapy due to the absence of a progressive disease assessment per RANO-HGG criteria, an apparent initial increase in tumor size per RAPNO and RANO-LGG criteria was subsequently followed by a sustained decrease in size, suggesting that the initial apparent increase may not represent true progression. HGG, high-grade glioma; LGG, low-grade glioma; PD, progressive disease; RANO, Response Assessment in Neuro-Oncology; RAPNO, Response Assessment in Pediatric Neuro-Oncology.

Extended Data Fig. 2. Swimlane plot of time to response and duration of therapy per RANO-LGG criteria.

In patients with response, symbols indicate the start of response (MR or PR). If initial response improved with continued treatment (from MR to confirmed PR), both the timepoint of the initial response and the timepoint that response initially improved are marked accordingly. BRAFi, BRAF inhibitor; LGG, low-grade glioma; MEKi, MEK inhibitor; MR, minor response; PR, partial response; RANO, Response Assessment in Neuro-Oncology.

Extended Data Fig. 3. Forest plot of response according to RAPNO in subgroups defined by baseline characteristics.

Filled circles represent the overall response rates, and whiskers represent the 95% confidence intervals. Other races included Asian (n = 5), Black (n = 2), Multiple (n = 3), and Other (n = 6). There were no Native Hawaiian or other Pacific Islander or American Indian or Alaska Native participants. No race information was missing. Ex, External to; US, United States.