CTNI-76 - Efficacy of BRAF inhibitor plixorafenib (FORE8394) in recurrent, primary central nervous system tumors (PCNST)

Friday, November 17, 2023

3:55 PM – 4:05 PM PT

Location: Room 109-110

Oral Abstract Presenter(s)

Macarena I. de la Fuente

Sylvester Comprehensive Cancer Center
Miami, Florida, United States

Author(s)

Nicholas A. Butowski

University of California San Francisco
San Francisco, California, United States
Jennie W. Taylor

University of California San Francisco
San Francisco, California, United States
RY

Rona Yaeger

Memorial Sloan Kettering Cancer Center
New York, New York, United States
FY

Frank Yung-Chin Tsai

Honor Health Research Institute
Scottsdale, Arizona, United States
FJ

Filip Janku

MD Anderson Cancer Center
Houston, Texas, United States
CA

Carl Allen

Baylor College of Medicine, Texas Children's Hospital
Houston, Texas, United States
NA

Natraj Ammakkanavar

Community Health Network, Cancer Center
Anderson, Indiana, United States
GM

Glenn Michelson

Fore Biotherapeutics
Philadelphia, Pennsylvania, United States
PJ

Ping Jiang

Fore Biotherpeutics
Philadelphia, Pennsylvania, United States
MP

Michael Paz

Fore Biotherapeutics
Philadelphia, Pennsylvania, United States
AT

Alexia Tussay-Lindenberg

Fore Biotherapeutics
Philadelphia, Pennsylvania, United States
KW

Kongming Wang

Fore Biotherapeutics
Philadelphia, Pennsylvania, United States
SP

Stacie Peacock Shepherd

Fore Biotherapeutics
Philadelphia, Pennsylvania, United States
IK

Irina Kline

Fore Biotherapeutics
Philadelphia, Pennsylvania, United States
ES

Eric Sherman

Memorial Sloan Kettering Cancer Center
New York, New York, United States
JR

Jordi Rodon

Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Houston, Texas, United States

Plixorafenib, a selective potent BRAFi, is uniquely designed to disrupt BRAF dimers and evade paradoxical MAPK pathway activation. Thus, it inhibits both V600 and non-V600 BRAF alterations and may be less prone to toxicities and resistance typical of approved BRAFi. An approved BRAFi, when used with MEKi, has ORR 33% with mDOR 13.6=months and ORR=50% with DOR of 6-29 months in V600+ HGG and LGG, respectively (dabrafenib US Prescribing Information, 2023). Phase 1/2a is a single-arm study (NCT02428712) in patients (n=113) with BRAF-altered advanced tumors to assess safety, PK, and efficacy of oral plixorafenib 900-3600 mg/day alone or with cobicistat (CYP3A4/P-gp inhibitor). Symptomatic TEAEs (rash, pyrexia, myalgia) were low grade and infrequent relative to approved BRAFi. This pre-specified analysis (31Mar2023) was in MAPKi-naïve adults with BRAFV600+ PCNST. 22 patients with PCNST received plixorafenib: 9 LGG, 1 glioneuronal tumor (LGG/GNT; 5 V600+), 12 HGG (10 V600+). Treatment-emergent AEs (TEAEs, ≥ 20%) were limited to LFT changes, G1 increased creatinine, fatigue, headache, and nausea. Only one G3 event (increased ALT) occurred at the RP2D (n=7) showing better tolerability than dabrafenib. 10 BRAFV600+ MAPKi-naïve adults with PCNST (median age 45 yrs, 6 females, 9 non-Hispanic) were efficacy evaluable: 6 HGG (4 glioblastoma, 1 epithelioid glioblastoma, 1 anaplastic astrocytoma); 4 LGG/GNT (1 each: ganglioglioma, pilocytic astrocytoma, xanthoastrocytoma, neuroepithelial tumor). Prior anti-cancer treatments included surgery (8/10), radiotherapy (8/10), and systemic therapy (8/10, including temozolomide [n=8], bevacizumab [n=2], carboplatin [n=1], dendritic cell vaccine [n=1]). 1 was treatment-naïve (unresectable; declined radiation/chemotherapy). ORR=60% (6/10) including HGG=67% (4/6), LGG/GNT=50% (2/4); median time to response=1.94 months; 4/6 responders with DOR > 9 months; mPFS=34.1 months; median follow-up=10.3 months; 4/10 ongoing. Plixorafenib has a benign safety profile and leads to a high ORR and durable response in MAPKi-naïve BRAFV600+ PCNST. A phase 2 study is ongoing to confirm these findings (NCT05503797).