Tovorafenib for Children with Optic Pathway Glioma: New Hope for Tumor Control and Vision Preservation

Table of Contents

• Key Points
• Understanding Optic Pathway Glioma: Why This Research Matters
• Study Methods: How the FIREFLY-1 Trial Was Conducted
• Who Were the Patients in This Analysis?
• Key Findings: How Well Did Tovorafenib Shrink Tumors?
• Key Findings: What Happened to Patients' Vision?
• Safety Profile: Was Tovorafenib Well Tolerated?
• What This Means for Patients and Families
• Study Limitations: What This Research Could Not Prove
• Recommendations and Questions for Your Child's Doctor
• Frequently Asked Questions
• Source Information

Key Points

• In FIREFLY-1, tovorafenib shrank tumors in 50–64% of 42 children with relapsed or resistant BRAF-altered optic pathway gliomas.
• Vision was preserved or improved in 80% of patients and 87% of eyes; some improved even with modest tumor shrinkage.
• Tovorafenib was generally well tolerated; most children stayed on treatment for a median of 16 months.
• A phase 3 trial is now testing tovorafenib as first-line therapy compared with standard chemotherapy.

Understanding Optic Pathway Glioma: Why This Research Matters

Low-grade glioma (LGG) is the most common type of central nervous system tumor in children. Approximately one-third of all pediatric low-grade gliomas (pLGGs) are located in the optic pathway and hypothalamic region of the brain, where they are specifically called optic pathway gliomas (OPGs). These tumors grow along the nerves that carry visual information from the eyes to the brain.

Because of where they sit, OPGs are rarely curable with surgery. While some pLGGs located in the back of the brain or in the cerebral hemispheres can be completely removed with surgery, attempting to remove an OPG would often cause serious functional damage—including worsened vision, hormonal (endocrinologic) problems, and movement (motor) deficits.

Children with OPGs who need treatment—usually because the tumor is growing and/or vision is threatened—are most often treated with systemic therapy (medicines that travel through the bloodstream). Many of these children require several lines of therapy over the first two decades of life, which can build up significant side effects over time. Meanwhile, tumor progression itself can cause or worsen functional problems, including vision loss.

About half of all OPGs occur in children with neurofibromatosis type 1 (NF1), an inherited tumor predisposition syndrome. Symptoms in these children typically appear before 6 years of age. Importantly, OPGs that occur sporadically (in children without NF1) are more likely to progress and more frequently require treatment. While some children with OPG may not need active intervention, anticancer treatment is generally recommended for patients with visual deterioration, because preserving visual function is critical for quality of life and for participating in age-appropriate activities.

First-line treatment for children with OPG typically consists of chemotherapy. Radiation therapy is generally avoided where possible due to serious long-term side effects, which can include visual disturbance, hormone deficiencies, cognitive impairment, and secondary cancers. Interestingly, the impact of chemotherapy on vision in sporadic OPG is still not fully clear due to differences in how studies are designed and how outcomes are measured. However, adding the drug bevacizumab to later lines of chemotherapy has shown promise for providing short-term disease control and may lead to visual improvement or preservation.

Like pLGGs in general, sporadic OPGs are commonly driven by genetic alterations in the BRAF gene, including KIAA1549::BRAF fusions and BRAF V600E point mutations. These alterations cause the mitogen-activated protein kinase (MAPK) signaling pathway to become overactive, driving tumor growth. This makes BRAF an attractive target for precision cancer therapies.

Study Methods: How the FIREFLY-1 Trial Was Conducted

The FIREFLY-1 trial (also known as PNOC026; clinical trial number NCT04775485) is an ongoing, open-label, phase 2 study with three arms. It evaluates the investigational drug tovorafenib—an oral, selective, brain-penetrant type II RAF inhibitor—given as a single agent to children, adolescents, and young adults with RAF-altered pLGGs or advanced solid tumors who had already received at least one prior systemic therapy.

Arm 1 of the trial enrolled patients with relapsed or refractory pLGG that harbored an activating BRAF alteration, including BRAF V600 mutations and KIAA1549::BRAF fusions. Arm 2 was a pLGG expansion cohort that provided treatment access for patients with RAF-altered pLGG after arm 1 closed. Both arms are now fully enrolled.

Tovorafenib was given at 420 mg/m² (not exceeding 600 mg) by mouth, once weekly, in 28-day cycles. Treatment continued until there was radiological evidence of disease progression, unacceptable side effects, or the patient chose to stop. Interestingly, patients whose disease progressed were allowed to keep taking tovorafenib if their doctor felt they were still getting clinical benefit. Treatment was planned for 26 cycles, after which patients could continue the drug or take a "drug holiday." If tumors grew again during the holiday, patients could restart tovorafenib.

How Tumor Response Was Measured

In the main analysis, tumor response was assessed using three different sets of radiological criteria:

• RANO-HGG (Response Assessment in Neuro-Oncology high-grade glioma) – primarily based on T1-weighted contrast-enhanced MRI images (looking at areas where the tumor "lights up" with contrast dye)
• RAPNO (Response Assessment in Pediatric Neuro-Oncology-LGG) – based on non-enhancing disease seen on T2/FLAIR MRI sequences, and includes a "minor response" (MR) category
• RANO-LGG – also based on T2/FLAIR imaging, with an MR category

The primary endpoint in arm 1 was the overall response rate (ORR)—the percentage of evaluable patients whose best confirmed response was a complete response (CR, tumor disappears) or partial response (PR, tumor shrinks significantly)—assessed by an independent radiology review committee (IRC) using RANO-HGG criteria. Secondary endpoints included ORR per RAPNO criteria, clinical benefit rate (CBR), progression-free survival, duration of response (DOR), and time to response (TTR). For RAPNO and RANO-LGG, an ORR could include CR, PR, or MR. The clinical benefit rate included CR, PR, MR, or stable disease (SD, meaning tumor stayed the same size for any length of time, or for at least 12 months in one calculation method).

How Vision Was Assessed

Visual acuity (VA—how clearly a child can see) was tested in each eye separately. Testing methods were age-specific and included Teller Acuity Cards for younger children and HOTV or Early Treatment Diabetic Retinopathy Study (ETDRS) charts for children who were developmentally able to perform them. The same testing method was recommended throughout treatment to reduce variability. Results were reported as logMAR scores, where 0 represents normal vision and positive numbers indicate reduced vision (for example, 0.2–0.5 indicates mild impairment, while 1.0–1.3 indicates severe impairment).

Vision response was defined as a decrease from baseline of at least 0.2 logMAR (meaning meaningful improvement) confirmed at two consecutive visits about 12 weeks apart. Progressive vision loss was defined as an increase of at least 0.2 logMAR at two consecutive assessments. Values in between were considered stable.

Ethical Conduct

The trial was approved by an institutional review board or independent ethics committee at each trial site. All patients and/or their legal representatives provided written informed consent, and children gave their assent before enrolling. The study was conducted in accordance with current ethical principles and trial standards.

Who Were the Patients in This Analysis?

Between May 6, 2021, and April 11, 2022, 42 of the 77 patients in arm 1 were found to have optic pathway tumor involvement, making OPG the largest tumor-location subgroup in the trial. This post hoc (after-the-fact) subgroup analysis focuses specifically on these 42 patients.

Key characteristics of the 42 OPG patients included:

• Median age: 8 years (range 2–16 years)
• Gender: 57% male (24 patients), 43% female (18 patients)
• Race: 57% White, 5% Asian, 2% Black, 5% multiple races, 7% other, 24% not specified
• BRAF alteration type:
• 81% (34 patients) had a KIAA1549::BRAF fusion
• 7% (3 patients) had another BRAF chromosomal rearrangement
• 12% (5 patients) had a BRAF V600E mutation
• Prior treatment: Median of 3 lines of prior systemic therapy (range 1–9 lines)
• Prior MAPK-targeted therapy: 67% had received a prior MEK inhibitor, 7% a prior BRAF inhibitor, and 5% had received both
• Functional status: 98% had a Lansky performance score of 80–100 (meaning most children were quite functional and active)

Notably, children with a known or suspected diagnosis of NF1 were excluded from the trial, so this analysis specifically reflects outcomes in children with sporadic OPGs—the group that tends to have more aggressive tumor behavior.

Of the 42 OPG patients, 35 had at least two visual acuity assessments and were included in the vision analysis. Seven patients were excluded from vision analysis for the following reasons: 4 had no VA assessments because they were bilaterally blind, 1 had no baseline visual assessment, 1 had no assessment after baseline, and 1 was deemed "not evaluable" due to uncooperativeness at testing sessions. Of the 35 evaluable patients, 18 were blind in one eye.

At baseline, among the 52 eyes that could be evaluated (both eyes for the 17 patients with vision in both eyes, plus the healthy eye for the 18 one-eye-blind patients):

• 29% (15 eyes) had normal vision (logMAR up to 0.19)
• 38% (20 eyes) had mild impairment (logMAR 0.2–0.5)
• 12% (6 eyes) had moderate impairment (logMAR 0.6–0.9)
• 12% (6 eyes) had severe impairment (logMAR 1.0–1.3)
• 2% (1 eye) had profound impairment (logMAR 1.4–1.6)
• 6% (3 eyes) could only count fingers (logMAR 1.7–2.0)
• 2% (1 eye) had only hand-motion vision (logMAR 2.1–2.4)

This means many of these children already had significant visual compromise before starting tovorafenib, making the vision outcomes especially meaningful. The median starting dose of tovorafenib was 420 mg/m² (range 290–476 mg/m²), and the median duration of treatment was 16 months.

Key Findings: How Well Did Tovorafenib Shrink Tumors?

Among the 42 OPG patients, 39 had measurable disease at baseline according to RANO-HGG criteria and were evaluable for response using that method. All 42 had measurable disease according to RAPNO and RANO-LGG criteria.

The tumor response rates were impressive across all three radiological criteria sets:

• RANO-HGG criteria: Overall response rate of 64% and clinical benefit rate of 95%
• RAPNO criteria: Overall response rate of 50% and clinical benefit rate of 88%
• RANO-LGG criteria: Overall response rate of 55% and clinical benefit rate of 90%

In plain terms, the large majority of children (88–95%) achieved either tumor shrinkage or at least stable disease—meaning their tumor stopped growing—while on tovorafenib. About half or more had confirmed substantial tumor reduction.

Waterfall plots of the best tumor response showed that most tumors shrank to some degree, whether measured by T1-weighted contrast-enhanced imaging (RANO-HGG) or by T2/FLAIR imaging (RAPNO and RANO-LGG). Tumor shrinkage occurred both in OPGs with BRAF fusions and those with BRAF V600E mutations. Importantly, responses were also seen both in patients who had previously received MAPK pathway inhibitor therapy (such as MEK inhibitors) and in those who had not—suggesting tovorafenib can work even after other targeted treatments have stopped being effective.

Some responses deepened over time. In 11 patients (26%), an initial minor response (MR) according to RAPNO criteria was later followed by a confirmed partial response (PR) with continued treatment. This tells us that tumor shrinkage can take time, and staying on treatment matters—some tumors that start shrinking slowly will eventually shrink significantly.

The duration of therapy and timing of responses demonstrated that these were durable, ongoing responses. At the data cutoff date of June 5, 2023, 69% of the OPG subgroup (29 of 42 patients) were still on treatment.

Key Findings: What Happened to Patients' Vision?

For a tumor located in the optic pathway, vision is arguably the most important outcome of all. The FIREFLY-1 trial made a point of formally tracking visual acuity before, during, and after treatment, and the results are highly encouraging.

Vision preservation per patient: Visual acuity was preserved (stable or improved) in 80% of the 35 evaluable patients. More specifically:

• 31% of patients experienced improved vision (a confirmed decrease in logMAR of at least 0.2 at two consecutive visits)
• 49% of patients had stable vision
• 20% of patients experienced worsening of vision

Vision preservation per eye: Looking at individual eyes rather than patients, vision was preserved in 87% of eyes:

• 27% of eyes improved
• 60% of eyes remained stable
• 13% of eyes worsened

These improvements occurred regardless of how good or bad the patient's baseline vision was (completely blind eyes were excluded from this calculation, since they could not improve). Vision changes also happened regardless of the time since the original diagnosis. Perhaps most remarkably, some patients experienced visual improvement even when their tumor showed only small changes in size on MRI. This suggests that tovorafenib may be protecting or even restoring vision through mechanisms beyond simple tumor shrinkage—finding ways to relieve pressure on the optic nerves, reduce inflammation, or otherwise support visual function.

When researchers analyzed how well tumor response and vision response matched up, they found both full concordance (both parameters improving or both stable) and partial concordance (one improving while the other was stable) in many patients. This reinforces the idea that radiological response and visual function are related but distinct benefits of treatment.

Safety Profile: Was Tovorafenib Well Tolerated?

In the 42-patient OPG subgroup, the safety profile of tovorafenib was similar to that seen in the overall FIREFLY-1 safety analysis set of 137 patients with pLGG. The trial carefully tracked adverse events of special interest (AESI), including rhabdomyolysis/myopathy (muscle breakdown or damage), ventricular arrhythmias (heart rhythm problems), intratumoral hemorrhage (bleeding inside the tumor), secondary primary malignancies (new cancers), ophthalmologic events (eye-related side effects), and decreased growth velocity. These events were reviewed and adjudicated for clinical relevance by an independent safety physician.

Among the 35 patients in the vision analysis set, the treatment discontinuation picture was as follows at the data cutoff:

• 69% (24 patients) were still on tovorafenib treatment
• 9% (3 patients) had discontinued due to disease progression
• 9% (3 patients) had discontinued due to adverse events
• 9% (3 patients) had withdrawn from the study
• 6% (2 patients) were on a drug holiday, one of whom had restarted treatment due to disease progression

Overall, most patients stayed on treatment for many months, and only a small proportion stopped because of side effects. The fact that most patients remained on therapy at 16+ months suggests that tovorafenib was generally well tolerated over the long term.

What This Means for Patients and Families

These findings are important for several reasons. First, optic pathway gliomas in children without NF1 tend to behave more aggressively and are more likely to require treatment. The fact that 88–95% of the children in this study achieved clinical benefit (tumor shrinkage or stability) after having already progressed through a median of three prior treatment lines is genuinely encouraging.

Second, and perhaps most importantly, vision was preserved in 80% of patients and 87% of eyes, with roughly one-third of patients and one-quarter of eyes actually seeing improvement. For a disease that threatens the most important sensory function in a child's development, this combination of tumor control and visual preservation is exactly what patients and families hope for.

The observation that some children's vision improved even when their tumor only shrank slightly is a critical insight. It suggests that visual acuity should be tracked carefully in children treated with tovorafenib—improvements may occur even when MRI results look modest. For families, this means "stable tumor on scan" is not the only good outcome to hope for; better vision may be possible even without dramatic tumor shrinkage.

Because this was a subgroup analysis of a phase 2 trial, the results are descriptive rather than confirmatory. However, they were strong enough to support the launch of the ongoing phase 3 LOGGIC/FIREFLY-2 trial (NCT05566795), which is comparing tovorafenib against standard-of-care chemotherapy in children with pLGG who need first-line systemic treatment. If those results confirm the findings seen here, tovorafenib could become an important new option for children with BRAF-altered gliomas, potentially moving from later-line treatment to earlier use.

Study Limitations: What This Research Could Not Prove

It is important to understand what this study can and cannot tell us:

• Subgroup analysis: This was a post hoc (after-the-fact) analysis of a subgroup within a phase 2 trial. It was not a randomized controlled trial and was not designed to compare tovorafenib against other treatments. The analyses were descriptive, and subgroups were not powered for statistical comparisons.
• No NF1 patients: The trial excluded patients with NF1, so these results apply to sporadic OPGs. Since about half of all OPGs occur in children with NF1, separate studies are needed for that population.
• Visual field testing: The study assessed visual acuity but did not routinely test visual fields (peripheral vision) or optic disc appearance in a standardized way. Visual acuity is only one part of overall visual function.
• Limited VA evaluability: Only 35 of 42 OPG patients could be evaluated for vision outcomes; the others were blind in both eyes, missing assessments, or uncooperative. Testing young children's vision can be challenging, which can introduce variability.
• Relatively small numbers: With 42 patients (and 52 evaluable eyes), the sample size is modest. Larger studies are needed to confirm these findings.
• No long-term follow-up yet: While median treatment duration was 16 months, longer follow-up is needed to understand durability of responses and long-term side effects, including impact on growth velocity and the risk of secondary malignancies.

Recommendations and Questions for Your Child's Doctor

Based on these findings, here are some key takeaways for families facing an optic pathway glioma diagnosis:

1. Ask about genomic testing. Because tovorafenib targets tumors with specific BRAF alterations (fusions or V600E mutations), knowing your child's tumor genetics is essential. Ask whether your child's tumor has been tested for BRAF alterations.
2. Consider a referral to a pediatric neuro-oncology center. These tumors are rare and complex, and specialized centers are most likely to offer access to clinical trials and multidisciplinary care involving neurologists, ophthalmologists, and endocrinologists.
3. Advocate for regular, careful vision testing. This study shows that vision can improve even when MRI changes are modest. Regular visual acuity assessments by a pediatric ophthalmologist should be a standard part of your child's care.
4. Discuss clinical trial options. The phase 3 LOGGIC/FIREFLY-2 trial (NCT05566795) is currently investigating tovorafenib as a first-line treatment compared with standard-of-care chemotherapy. Your child may be eligible for this or other trials.
5. Be patient with treatment. In this study, some responses took time to develop—26% of patients went from a minor response to a confirmed partial response with continued treatment. Early stability without shrinkage is still a meaningful result.
6. Ask about vision as an outcome. When discussing treatment options, ask your child's care team: "What is this treatment's track record for preserving or improving vision?" Tumor size on MRI is not the only thing that matters.
7. Understand the safety profile. Tovorafenib is generally well tolerated, but ask about monitoring for muscle issues, eye side effects, heart rhythm changes, bleeding in the tumor, and growth. Knowing what to watch for empowers families to report symptoms early.

Every child's situation is unique. What works for one patient may not be right for another. The decision about whether to try tovorafenib—and when in the treatment journey to use it—should be made together with your child's oncology team, taking into account the tumor's specific genetic drivers, the child's overall health, prior treatments, and current visual function.

Frequently Asked Questions

What is an optic pathway glioma and why does this research matter?

Optic pathway gliomas are brain tumors near the nerves connecting eyes to the brain. They can threaten vision and are rarely curable with surgery. Many children need multiple treatments over decades. This research focuses on a targeted therapy that may shrink tumors and preserve vision in children with relapsed or resistant tumors.

How well did tovorafenib shrink tumors in the FIREFLY-1 trial?

In the FIREFLY-1 trial, among 42 children with optic pathway glioma, tumor shrinkage or stable disease occurred in 88–95% of patients. Confirmed substantial tumor reduction was seen in 50–64%, depending on the radiological criteria used. Responses occurred in children with BRAF fusions or mutations, including those who had previous targeted therapy.

What happened to vision in children treated with tovorafenib?

In the trial, vision was preserved (stable or improved) in 80% of patients and 87% of eyes evaluated. Specifically, 31% of patients and 27% of eyes improved, while 49% of patients and 60% of eyes remained stable. Even some children with modest tumor shrinkage experienced visual improvement.

What are the side effects of tovorafenib?

In this trial, most patients stayed on treatment for a median of 16 months. Only a small proportion stopped due to side effects. Monitoring included muscle issues, heart rhythm changes, bleeding in the tumor, eye side effects, and growth. Always discuss specific risks with your child's oncology team.

Can tovorafenib be used after other treatments have stopped working?

Yes. In the FIREFLY-1 trial, children had received a median of 3 prior lines of therapy. Some had previously taken MEK or BRAF inhibitors. Tovorafenib produced tumor shrinkage and vision preservation even in this group, suggesting it can be effective after other treatments have failed.

How was vision tested in children in the trial?

Vision was tested separately in each eye using age-appropriate methods. Young children used Teller Acuity Cards; older or developmentally able children used HOTV or ETDRS charts. The same method was recommended throughout treatment to reduce variability. Meaningful improvement or worsening was defined as a 0.2 logMAR change confirmed at two visits.

What is the phase 3 LOGGIC/FIREFLY-2 trial?

The phase 3 LOGGIC/FIREFLY-2 trial (NCT05566795) is an ongoing study comparing tovorafenib with standard-of-care chemotherapy as first-line treatment in children with low-grade glioma. It was launched based on strong results from the FIREFLY-1 trial. Families should discuss eligibility with their child's oncology team.

Can a second opinion change the treatment plan for a child with relapsed optic pathway glioma who is considering tovorafenib?

For a child with relapsed or treatment-resistant BRAF-altered optic pathway glioma, a second opinion can clarify whether tovorafenib is a reasonable next option. In the FIREFLY-1 trial, 50–64% of children had confirmed tumor shrinkage and 88–95% achieved clinical benefit, while vision stayed stable or improved in 80% of patients and 87% of eyes. A second opinion can review the tumor's BRAF status, MRI and visual assessments, and weigh tovorafenib against other therapies or clinical trials, including first-line trials if the child has not yet received treatment. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Radiographic and visual response to the type II RAF inhibitor tovorafenib in children with relapsed/refractory optic pathway glioma in the FIREFLY-1 trial.

Authors: Nysom K, Kilburn LB, Leary SES, Landi DB, de Vos-Kerkhof E, Perreault S, Witt O, Ziegler DS, Hernáiz Driever P, Franson AT, Baxter PA, Whipple NS, Kline C, Segal D, Jabado N, Bailey S, McCowage G, Hansford JR, Khuong-Quang DA, Gottardo NG, Hassall T, Han JW, Yalon Oren M, Chi SN, Qiu J, Da Costa D, Govinda Raju S, Manley P, Hargrave D.

Journal: Neuro-Oncology, Volume 27, Issue 5, pages 1341–1355, 2025

Publication details: Published by Oxford University Press on behalf of the Society for Neuro-Oncology. Advance Access date: December 19, 2024. DOI: https://doi.org/10.1093/neuonc/noae274. Open Access under Creative Commons Attribution License.

Corresponding author: Karsten Nysom, MD, PhD, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Denmark.

Clinical trial registration: FIREFLY-1 (PNOC026), NCT04775485. This patient-friendly article is based on peer-reviewed research. It is intended for informational purposes only and does not constitute medical advice. Always consult your child's oncology team about individual treatment decisions.