FDA Accepts NDA for Tovorafenib in Pediatric Low-Grade Glioma

• The new drug application (NDA) of tovorafenib (DAY101) as a monotherapy in the treatment of relapsed or progressive pediatric low-grade glioma (pLGG) was accepted by the FDA.
• The FDA granted tovorafenib priority review, which means the FDA aims to take action on the application within 6 months instead of the standard 10 months.
• A Prescription Drug User Fee Act target action date of April 30, 2024, has been set, and no advisory committee meetings to discuss the application are currently planned.

Glioma cancer tumor: ©freshidea - stock.adobe.com

The FDA accepted the NDA of tovorafenib, an oral, highly selective type II RAF kinase inhibitor, as a single-agent treatment for patients with relapsed or progressive pLGG, according to Day One Biopharmaceuticals, tovorafenib’s manufacturer.¹

The NDA is based on findings from the open-label phase 2 FIREFLY-1 trial (NCT04775485).² Among the 69 evaluable patients treated with tovorafenib, an overall response rate (ORR) of 67% per Response Assessment for Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria was reached, along with a clinical benefit rate of 93%. This included a complete response rate of 17%, a partial response rate of 49%, and a stable disease rate of 26%.

Additionally, the median duration of response (DOR) was 16.6 months (95% CI, 11.6-not estimable [NE]) per RANO-HGG criteria.

“We are pleased to be one step closer to achieving our mission of bringing a novel targeted therapy to children whose low-grade gliomas with BRAF alterations have relapsed or progressed,” said Jeremy Bender, PhD, chief executive officer of Day One, in a press release.¹

The trial has an estimated enrollment of 140 patients aged 6 months to 25 years with progressive or recurrent pLGG. Arm 1 of the trial includes patients with a known BRAF alteration, including BRAF V600 mutations. Arm 2 includes patients with a known or expected RAF alteration. Arm 3 includes patients with advanced solid tumors with a known or expected RAF fusion. In the trial, patients are receiving 100 mg of tovorafenib in an immediate release tablet or 25 mg/mL as a power for reconstitution.

The primary end point for arm 1 is ORR by independent radiology review committee based on RANO criteria. The primary end point for arm 2 is tovorafenib’s safety and tolerability. The primary end point for arm 3 is ORR by independent radiology review committee based on RECIST v1.1 criteria. Secondary end points include the relationship between pharmacokinetics and drug effects, effects on electrocardiogram and QT interval, ORR by investigator, DOR, and time to response.

Patients were considered eligible if they had histological disease confirmation, evidence of radiographic progression after at least 1 line of systemic therapy, and at least 1 measurable lesion defined by RANO or RECIST v1.1. Patients were not eligible if their tumor had additional known activating molecular alterations, if the patient demonstrated clinical progression in the absence of radiographic progression, or if the patient had a known or suspected neurofibromatosis type 1 diagnosis.

The trial began in April 2021 and has an estimated completion date of February 2024.²

REFERENCES:

1. Day One announced FDA acceptance of NDA and priority review for tovorafenib in relapsed or progressive pediatric low-grade glioma (pLGG). News release. Day One Biopharmaceuticals. October 30, 2023. Accessed October 30, 2023. https://tinyurl.com/dka4d3ay

2. A study to evaluate DAY101 in pediatric and young adult patients with relapsed or progressive low-grade glioma and advance solid tumors (FIREFLY-1). ClinicalTrials.gov. Updated January 11, 2023. Accessed October 30, 2023. https://clinicaltrials.gov/study/NCT04775485