| Title: |
The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial |
| Authors: |
Kilburn, LB; Khuong-Quang, DA; Hansford, JR; Landi, D; van der Lugt, J; Leary, SES; Driever, PH; Bailey, S; Perreault, S; McCowage, G; Waanders, AJ; Ziegler, DS; Witt, O; Baxter, PA; Kang, HJ; Hassall, TE; Han, JW; Hargrave, D; Franson, AT; Yalon Oren, M; Toledano, H; Larouche, V; Kline, C; Abdelbaki, MS; Jabado, N; Gottardo, NG; Gerber, NU; Whipple, NS; Segal, D; Chi, SN; Oren, L; Tan, EEK; Mueller, S; Cornelio, I; McLeod, L; Zhao, X; Walter, A; Da Costa, D; Manley, P; Blackman, SC; Packer, RJ; Nysom, K |
| Source: |
Nature Medicine (2023) (In press). |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2023 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
Drug development; Paediatric cancer; Phase II trials; Randomized controlled trials; Targeted therapies |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10182485/1/Hargrave_The%20type%20II%20RAF%20inhibitor%20tovorafenib%20in%20relapsed_VoR.pdf; https://discovery.ucl.ac.uk/id/eprint/10182485/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10182485/1/Hargrave_The%20type%20II%20RAF%20inhibitor%20tovorafenib%20in%20relapsed_VoR.pdf; https://discovery.ucl.ac.uk/id/eprint/10182485/ |
| Rights: |
open |
| Accession Number: |
edsbas.B042311F |
| Database: |
BASE |