FDA Approves Companion Diagnostic for Tovorafenib in BRAF-Altered Pediatric Low-Grade Glioma

The FDA has approved the FoundationOne CDx test for use as a companion diagnostic to assess BRAF alteration status in pediatric patients at least 6 months of age with relapsed/refractory low-grade glioma, and identify those eligible for treatment with tovorafenib (Ojemda).1

On April 23, 2024, the FDA granted accelerated approval to tovorafenib for the treatment of pediatric patients 6 months of age or older with relapsed/refractory low-grade glioma harboring a BRAF rearrangement or fusion, or a BRAF V600 mutation.2

“Foundation Medicine is proud to partner with Day One to help health care providers connect pediatric patients and families with this treatment option,” Mia Levy, MD, PhD, chief medical officer at Foundation Medicine, stated in a news release.1 “Our high-quality tissue-based companion diagnostic test is uniquely capable of detecting both BRAF V600 mutations and fusions, which enables providers to gain the complete genomic picture of their patient’s tumor and guide treatment decision-making.”

The FDA approval of tovorafenib was backed by findings from arm 1 of the multicenter, single-arm, open-label phase 2 FIREFLY-1 trial (NCT04775485), which enrolled patients 6 months to 25 years of age who had relapsed/refractory pediatric low-grade glioma and displayed an activating BRAF alteration, as detected by local assessment.2,3 Patients were required to have received at least 1 prior line of systemic therapy, have documented evidence of radiographic progression, and at least 1 measurable lesion per Response Assessment in Neuro-Oncology (RANO) criteria.

Patients received oral tovorafenib at the recommended phase 2 dose of 420 mg/m2 up to a maximum dose of 600 mg once weekly on days 1, 8, 15, and 22 of a 28-day cycle. Treatment continued until disease progression or unacceptable toxicity.4

The primary end point of arm 1 of FIREFLY-1 was independent review committee (IRC)–assessed overall response rate (ORR) per RANO–High-Grade Glioma (HGG) criteria. Key secondary end points included IRC-assessed ORR by Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, duration of response (DOR), clinical benefit rate, progression-free survival, investigator-assessed ORR, time to response, and safety.

Data that supported the approval showed that among 76 evaluable patients who received tovorafenib, the ORR per RAPNO criteria was 51% (95% CI, 40%-63%), and the median DOR was 13.8 months (95% CI, 11.3-not estimable).2

Additional data from FIREFLY-1 showed that among 69 patients in arm 1 with measurable disease at baseline per RANO-HGG criteria, the ORR per RANO-HGG criteria was 67% (95% CI, 54%-78%), including a complete response rate of 17% and a partial response rate of 49%.4 The ORR was 69% (95% CI, 56%-81%) in patients with tumors harboring BRAF fusions and 50% (95% CI, 19%-81%) in those with tumors harboring BRAF V600E mutations.

The most common any-grade adverse effects (AEs) included changes in hair color, rash, viral infection, fatigue, headache, vomiting, pyrexia, hemorrhage, constipation, dry skin, dermatitis acneiform, nausea, and upper respiratory tract infection.2 Notably, grade 3/4 laboratory abnormalities were also reported.

The FDA-recommended dose of tovorafenib is 380 mg/m2 once weekly, and the maximum recommended dose is 600 mg once weekly. Notably, the recommended dose of the agent for patients with a body surface area smaller than 0.3 m2 has not been determined.

“Historically, pediatric patients with pediatric low-grade glioma have faced overwhelming AEs, both near- and long-term, from aggressive treatments like chemotherapy and radiation,” David Arons, president and CEO at the National Brain Tumor Society, added in the news release.1 “We are thrilled to see that there are now additional treatment options available for these children, as well as an FDA-approved companion diagnostic test to help identify more patients who may benefit from Day One’s therapy.”

References

1. U.S. Food and Drug Administration approves FoundationOneCDx as a companion diagnostic for Ojemda (tovorafenib) to treat the most common form of childhood brain tumor in pediatric patients. News release. Foundation Medicine, Inc. January 17, 2025. Accessed January 17, 2025. https://www.foundationmedicine.com/press-release/fda-approval-foundationone-cdx-ojemda
2. FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma. FDA. April 23, 2024. Accessed January 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tovorafenib-patients-relapsed-or-refractory-braf-altered-pediatric
3. 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 December 27, 2023. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT04775485
4. Kilburn LB, Khuong-Quang DA, Hansford JR, et al. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Nat Med. 2024;30(1):207-217. doi:10.1038/s41591-023-02668-y