Tovorafenib Shows Durable Off-Treatment Responses in Pediatric BRAF-Altered Low-Grade Glioma
核心洞察
Tovorafenib (Ojemda) demonstrates durable responses in pediatric patients with BRAF (搜索)-altered relapsed/refractory low-grade glioma (搜索) during drug holidays in the FIREFLY-1 trial.
97% of patients on a drug holiday showed no clinical progression, with 15% experiencing additional tumor shrinkage of at least 25%.
The safety profile of tovorafenib remained consistent in patients rechallenged after a drug holiday, with retreatment ongoing in some cases.
Treatment with the type II RAF inhibitor tovorafenib (Ojemda) has shown durable responses in pediatric patients with BRAF (搜索)-altered relapsed/refractory low-grade glioma (搜索) who entered a drug holiday during the phase 2 FIREFLY-1 trial (NCT04775485). These findings were presented at the 2024 Society for Neuro-Oncology (搜索) Annual Meeting.
At the data cutoff of May 10, 2024, among the 33 patients who entered a drug holiday, 97% experienced no signs of clinical progression, and 15% achieved additional tumor shrinkage of at least 25%. Furthermore, 91% of patients remained on a drug holiday, with only one patient showing signs of clinical progression. The safety profile of tovorafenib in the three patients rechallenged with the drug following a drug holiday was consistent with its known safety profile. The median duration of treatment was 24 months (range, 16-29), and the median follow-up since the end of treatment was 3.4 months (range, 0.3-10.6).
FIREFLY-1 Trial Details
The FDA granted accelerated approval to tovorafenib in April 2024 for pediatric patients aged 6 months and older with relapsed or refractory low-grade glioma (搜索) harboring a BRAF (搜索) fusion or rearrangement, or a BRAF V600 mutation. This decision was based on earlier data from the FIREFLY-1 trial, marking the first systemic therapy indication for pediatric low-grade glioma with BRAF rearrangements, including fusions.
FIREFLY-1 is an ongoing multicenter, open-label trial evaluating the safety and efficacy of tovorafenib in pediatric, adolescent, and young adult patients with recurrent or progressive low-grade glioma (搜索) or advanced solid tumors with a known RAF alteration. The trial includes three arms: patients with recurrent or progressive low-grade glioma harboring an activating BRAF (搜索) alteration (including BRAF V600 mutations and KIAA1549:BRAF fusions), patients with recurrent or progressive low-grade glioma harboring a known or expected activating RAF alteration, and patients with advanced solid tumors harboring a known or expected activating RAF fusion. Key inclusion criteria include radiographic disease progression following at least one line of systemic therapy and at least one measurable lesion per Response Assessment in Pediatric Neuro-Oncology (RANO) or RECIST 1.1 criteria.
Patients receive oral tovorafenib at a dose of 420 mg/m2 once weekly (not exceeding 600 mg) for each 28-day treatment cycle, administered for a planned period of 26 cycles (approximately 24 months). Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint in arms 1 and 3 is overall response rate (ORR) by independent radiology review committee (IRC) based on RANO criteria. In arm 2, the primary endpoint is safety and tolerability. Secondary endpoints include pharmacokinetics, investigator-assessed ORR, progression-free survival, duration of response, time to response (TTR), and clinical benefit rate.
The drug holiday analysis aimed to assess the stability of response and the need for additional treatment in patients who completed at least two years of tovorafenib treatment and to determine whether patients could be rechallenged with tovorafenib following disease progression during the holiday.
Key Findings from Drug Holiday Analysis
The median age of patients entering a drug holiday was 8 years (range, 3-16). The majority were male (58%), with BRAF (搜索) alterations including BRAF fusions (88%) – primarily KIAA 1549:BRAF fusions (73%) and other BRAF fusions (15%) – and BRAF V600E mutations (12%). The median number of prior lines of systemic therapy was 2 (range, 1-7), with 21% having received one prior line, 30% having received two, and 49% having received three or more.
One notable case involved a 15-year-old patient with a BRAF (搜索) V600E–mutated mid-brain, dorsal pons tumor who received tovorafenib at 600 mg weekly for 24.6 months. This patient achieved a partial response (PR) with a 67.1% tumor shrinkage and a median TTR of 2.73 months. Clinically relevant treatment-related adverse effects (TRAEs) included grade 2 keratosis pilaris, hypophosphatemia, and hypokalemia, as well as grade 1 increased creatine phosphokinase (CPK) levels, hair color change, rash, anemia, and hypocalcemia. Upon rechallenge with tovorafenib at 600 mg weekly, the patient achieved stable disease, with retreatment ongoing for over a month at the data cutoff and no reported TRAEs.
Another patient, a 6-year-old with BRAF (搜索) fusion–positive optic pathway glioma (搜索), received tovorafenib at 400 mg weekly for 23.7 months, achieving a PR with a 55.0% tumor shrinkage and a median TTR of 2.76 months. TRAEs included grade 2 rash, increased CPK levels, and decreased growth velocity, along with grade 1 hair color change, dermatitis, facial and limb edema, hypocalcemia, hypophosphatemia, increased liver function test levels, alopecia, anemia, paronychia, and cheilitis. During the drug holiday, the patient experienced disease progression after 8.5 months, with a 28% increase in tumor size. Rechallenged with tovorafenib at 500 mg weekly, the patient showed a 1.1% decrease in tumor size at first assessment, with no clinical progression. Retreatment was ongoing for over 3 months at data cutoff, with no reported adverse events since retreatment began.