CTNI-24 - Clinical activity and safety of the RAF inhibitor tovorafenib in patients with optic pathway gliomas in the registrational pediatric low-grade glioma arm of the phase 2 FIREFLY-1 (PNOC026) study

Friday, November 17, 2023

10:15 AM – 10:25 AM PT

Location: Exhibit Hall C

Plenary Abstract Presenter(s)

Karsten Nysom

Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital - Rigshospitalet
Copenhagen, Denmark

Author(s)

Lindsay B. Kilburn

Children’s National Hospital
Washington, District of Columbia, United States
Sarah E. S. Leary

Cancer and Blood Disorders Center, Seattle Children's
Seattle, Washington, United States
Daniel B. Landi

Duke University
Durham, North Carolina, United States
Ed

E. de Vos-Kerkhof

Princess Máxima Center for Pediatric Oncology
Utrecht, Netherlands
Sébastien Perreault

CHU Sainte Justine
Montréal, Quebec, Canada
OW

Olaf Witt

Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)
Heidelberg, Germany
David S. Ziegler

Kids Cancer Centre, Sydney Children’s Hospital
Randwick, New South Wales, Australia
PH

Pablo Hernáiz Driever

German HIT-LOGGIC-Registry for LGG in children and adolescents, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Berlin, Germany
Andrea T. Franson

University of Michigan
Ann Arbor, Michigan, United States
PB

Patricia A. Baxter

Texas Children's Cancer Center, Texas Children's Hospital
Houston, Texas, United States
NW

Nicholas S. Whipple

Primary Children’s Hospital, University of Utah
Salt Lake City, Utah, United States
Cassie Kline

Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
DS

Devorah Segal

NYU Langone Health
New York, New York, United States
NJ

Nada Jabado

Research Institute McGill University Health Centre (MUHC) - The Montreal Children's Hospital (MCH)
Montreal, Quebec, Canada
SB

Simon Bailey

Great North Childrens Hospital and Newcastle University
Newcastle upon Tyne, United Kingdom
GM

Geoffrey McCowage

Sydney Children’s Hospitals Network
Westmead, New South Wales, Australia
JH

Jordan R. Hansford

Children's Cancer Centre, Royal Children’s Hospital Melbourne
Parkville, Victoria, Australia
DK

Dong-Anh Khuong-Quang

The Royal Children's Hospital Melbourne
Melbourne, Victoria, Australia
NG

Nicholas G. Gottardo

Perth Children's Hospital
Perth, Australia
TH

Timothy Hassall

Children’s Health Queensland Hospital and Health Service
South Brisbane, Australia
JH

Jung Woo Han

Severance Hospital, Yonsei University Health System
Seoul, Republic of Korea
MY

Michal Yalon Oren

Sheba Medical Center
Ramat Gan, Tel Aviv, Israel
Susan N. Chi

Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
Boston, Massachusetts, United States
VL

Vai Lee

Day One Biopharmaceuticals
Brisbane, California, United States
LM

Lisa McLeod

Day One Biopharmaceuticals
Brisbane, California, United States
JQ

Jiaheng Qiu

Day One Biopharmaceuticals
Brisbane, California, United States
AW

Ashley Walter

Day One Biopharmaceuticals
Brisbane, California, United States
PM

Peter Manley

Day One Biopharmaceuticals
Brisbane, California, United States
DH

Darren Hargrave

UCL Great Ormond Street Institute of Child Health
London, England, United Kingdom

Background: Optic pathway gliomas (OPG) are low-grade gliomas (LGG) comprising 3-5% of pediatric brain tumors. Morbidity may include visual loss (acuity and visual fields), hypothalamic/pituitary dysfunction, and/or impaired motor function. Genomic alterations of MAPK/BRAF are frequent oncogenic drivers in pediatric LGG. Activity of tovorafenib, an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor in OPGs was analyzed.

Methods: FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib (420 mg/m² weekly) in patients 6 months–25 years with BRAF-altered recurrent/progressive LGG or solid tumors. Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints.

Results: Of the 77 patients enrolled in arm 1 (measurable disease per RANO-HGG), 42 (55%) had tumors located in the optic pathway. Median age at enrollment was 8 years (range: 2–16); 37 (88%) harbored a BRAF fusion and 5 (12%) a BRAF V600E mutation. The median prior lines of systemic therapy was 3 (range: 1–9), with 69% having received prior MAPK inhibitors. Of the 39 evaluable patients (RANO-HGG), the ORR was 59% (1 CR, 22 PRs) with a median time to response (TTR) of 2.8 months; 14 (36%) had stable disease (SD). Per RANO-LGG (n=42), the ORR was 43% (5 PRs; 13 MRs) with a median TTR of 4.1 months; 20 (48%) had SD. Visual acuity remained stable in 79% (23) of patients (Cycle 9, n=29 assessed). The most common treatment-related adverse events (TRAEs) of any grade in this subgroup were hair color changes (81%), increased creatine phosphokinase (55%), anemia (48%), maculopapular rash (45%), and fatigue (41%). Dose modifications occurred in 14 (33%) and discontinuations in 3 (7%) patients due to TRAEs.

Conclusions: Tovorafenib demonstrated antitumor activity in recurrent/progressive BRAF-altered OPG and was generally well tolerated. Visual acuity remained stable for the majority with OPGs.