Tovorafenib Sustains Treatment-Free Intervals in R/R BRAF-Altered Pediatric Low-Grade Glioma

Planned cessation of tovorafenib (Ojemda) led to durable treatment-free intervals in many patients with relapsed or refractory BRAF-altered pediatric low-grade glioma, according to findings from a 4-year analysis of the phase 2 FIREFLY-1 trial (NCT04775485) presented at the 2026 SNO Annual Meeting.¹

Per Response Assessment in Pediatric Neuro-Oncology low-grade glioma criteria and independent review, the objective response rate (ORR) was 53% among efficacy-evaluable patients in arm 1 (n = 76), and the clinical benefit rate per protocol was 58%.¹

Among patients who entered the post-treatment observation period (n = 41), 76% remained treatment free for at least 12 months, and 54% remained treatment free for at least 24 months; the median treatment-free interval was not reached. The median follow-up from the last tovorafenib dose to the start of subsequent anticancer therapy was 26.2 months (range, 1.4-36.5).

In efficacy-evaluable patients in arm 1 (n = 76), the median time to next treatment was 50.9 months (95% CI, 36.7-not estimable), and the median radiographic progression-free survival was 16.6 months (95% CI, 10.9-22.0). The median clinical progression-free survival (PFS) was not reached (NR; 95% CI, not estimable [NE]-NE).

“Something that’s relevant for many of us who [treat] these patients is the treatment-free interval [TFI],” Daniel Landi, MD, of Duke University and Duke Cancer Center in Durham, North Carolina, stated in a presentation of the data. “We intervene medically when a tumor is growing and causing a problem in a child. But our ultimate hope is to stop therapy for many of these patients. The 4-year dataset affirms the potency and efficacy of [tovorafenib].”

What was the design of the FIREFLY-1 trial of tovorafenib in pLGG?

FIREFLY-1 is open to patients from 6 months to 25 years of age who have relapsed or progressive low-grade glioma or advanced solid tumors with RAF alterations.² The analysis presented here used a data cutoff of June 5, 2026, with an updated median study duration of 52.5 months in arm 1.¹ Arm 1 was the registrational cohort for patients with BRAF-altered pediatric low-grade glioma (pLGG; n = 77), and arm 2 was an extension cohort (n = 60).

Patients received tovorafenib at 420 mg/m² (maximum, 600 mg) by mouth once weekly, with or without food, in 28-day cycles for a planned 26 cycles (approximately 24 months). After that period, patients could continue to receive tovorafenib or enter an optional post-treatment observation period off anticancer therapy at any point. The primary end point was objective response rate per Response Assessment in Neuro-Oncology high-grade glioma criteria. Secondary end points included safety; objective response rate (ORR) per Response Assessment in Pediatric Neuro-Oncology low-grade glioma criteria; clinical benefit rate; time to response; duration of response; and PFS per Response Assessment in Pediatric Neuro-Oncology low-grade glioma (RAPNO) criteria.

Time to next treatment (TTNT) and TFI were exploratory end points. TTNT captured the interval from the first tovorafenib dose until the next anticancer therapy, including retreatment with tovorafenib, or death, whereas TFI captured the interval from the last tovorafenib dose until subsequent treatment or death. Radiographic progression was a composite of tumor growth of at least 25% over the nadir, any new lesion, or death, and clinical progression was a composite of unequivocal neurologic or functional decline due to the tumor.

What did earlier FIREFLY-1 results show with tovorafenib in relapsed/refractory pLGG?

Tovorafenib is an oral, once-weekly type II RAF inhibitor that penetrates the central nervous system and is approved by the FDA under accelerated approval for the treatment of patients with relapsed or refractory BRAF-altered pLGG. Data from the primary analysis of FIREFLY-1 were published in 2024.³ In that analysis, the ORR per Response Assessment in Neuro-Oncology high-grade glioma criteria was 67% (95% CI, 54%-78%), which met the prespecified primary end point of arm 1. The ORR per RAPNO criteria, which includes minor responses, was 51% (95% CI, 40%-63%), the median duration of response (DOR) was 13.8 months (95% CI, 11.3-NR), and the median time to response (TTR) was 5.3 months (range, 1.6-11.2).

What did the 4-year FIREFLY-1 update show for response, radiographic progression, and retreatment with tovorafenib in pLGG?

The median DOR was 19.4 months (95% CI, 13.8-27.2), and the median TTR was 5.4 months (range, 1.6-17.5). In total, 58% of patients (n = 76) received at least 26 cycles of tovorafenib. Landi noted in the presentation that responses occurred quickly with tovorafenib and that the DOR lengthened with longer follow-up.

During treatment, 39 of the 76 patients had radiographic progressive disease per RAPNO criteria. Of these patients, 77% had a smaller tumor at the end of treatment than at baseline, and 46% had further tumor reduction beyond the point of progression.

“In most cases, [patients’] progressive disease [PD] event, radiographically, was still below their baseline scan, and 46% of patients had tumor response beyond their PD event,” Landi said. He added that “the transient increase was not a harbinger that the drug had failed or that the patient was going to progress,” and that the findings give “recourse to continue” treatment in a patient who is doing well, even when the MRI results appear worse.

Among the patients who entered post-treatment observation (n = 41), 38 had completed at least 26 cycles of tovorafenib. Tumor rebound was defined as growth of at least 25% within 6 months of the last dose, measured against the last scan before the final dose, and it occurred in 54% of patients; 46% of patients did not have rebound. The median change in tumor size from the end of treatment was 1% (IQR, −9% to 24%) at the first assessment and 2% (IQR, −7% to 25%) at the second assessment. Among patients with a BRAF V600E mutation, 5 of 13 had tumor rebound.

Eleven patients in the observation group (n = 41) received retreatment with tovorafenib, including 7 who were retreated after tumor rebound. The median duration of retreatment was 18 months (range, 4.4-25.8), the median number of cycles was 20 (range, 5-29), and 91% of retreated patients (n = 11) continued to receive retreatment at data cutoff. The median best change in tumor size from the start of retreatment was −41% (range, −81% to 5%), and 82% of patients (n = 11) had a smaller tumor at the last scan than before retreatment.

“These are tumors that are single-pathway, genetically simple tumors,” Landi explained in the presentation. “They tend not to acquire secondary mutations or transform molecularly. If you have a potent targeted therapy that works in the first instance, these data suggest that you’re likely to see a response on retreatment.”

What was the safety profile of tovorafenib in the 4-year FIREFLY-1 analysis in pLGG?

Among patients in the safety population (N = 137), treatment-emergent adverse effects of any grade occurred in 100%, and grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 82% (n = 113). Treatment-related adverse effects of any grade occurred in 99% of patients (n = 136), and grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 67% of patients (n = 92). TEAEs led to discontinuation in 14% of patients (n = 19), and TRAEs led to discontinuation in 13% of patients (n = 18). No treatment-related deaths occurred, and no additional discontinuations due to TRAEs occurred since the 3-year data cutoff.

The most common grade 3 or higher TRAEs, each occurring in at least 5% of patients, were reduced growth velocity (36%; n = 49), anemia (14%; n = 19), increased creatine phosphokinase levels (11%; n = 15), maculopapular rash (8%; n = 11), and increased alanine aminotransferase levels (5%; n = 7). Grade 3 or higher intratumoral hemorrhage occurred in 4% of patients (n = 5), and no patient had a left ventricular ejection fraction below 50% during treatment. In the growth analysis set (n = 90), 88% of patients (n = 79) had growth recovery, regardless of the degree of growth suppression during treatment.

“The safety and tolerability profile for [tovorafenib] remains very much the same from the registrational data set,” Landi contextualized in the presentation.

What are the next steps for evaluating tovorafenib in BRAF-altered pLGG after the 4-year FIREFLY-1 analysis?

Landi concluded that the 4-year analysis data support the clinical benefit and durability of tovorafenib that were seen in the 3-year analysis, that TTNT surpassed radiographic PFS and gave a fuller picture of benefit, and that radiographic progression was frequently followed by additional tumor shrinkage. He also reported that early data support retreatment and that the safety profile remained in line with prior findings.

As a next step, the phase 3 LOGGIC/FIREFLY-2 trial (NCT05566795) is evaluating tovorafenib monotherapy vs standard-of-care chemotherapy in patients with pLGG harboring an activating RAF alteration who require first-line systemic therapy.⁴ Enrollment to this trial has been completed, and data are expected in late 2027.¹

References

1. Landi D, Khuong-Quang DA, Nysom K, et al. Updated 4-year results from the phase 2 FIREFLY-1 study: deep responses and prolonged time off therapy with tovorafenib in relapsed/refractory pediatric low-grade glioma. Presented at: 2026 SNO Annual Meeting; November 12-15, 2026; Philadelphia, PA. Abstract CTP-02.
2. A study to evaluate tovorafenib in pediatric and young adult participants with relapsed or progressive low-grade glioma and advance solid tumors (FIREFLY-1). ClinicalTrials.gov. Updated April 10, 2025. Accessed November 14, 2026. https://clinicaltrials.gov/study/NCT04775485
3. 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
4. DAY101 vs. standard of care chemotherapy in pediatric participants with low-grade glioma requiring first-line systemic therapy (LOGGIC/​FIREFLY-2). ClinicalTrials.gov. Updated October 19, 2026. Accessed November 14, 2026. https://clinicaltrials.gov/study/NCT05566795