A critical review of RAF inhibitors in BRAF-mutated glioma treatment

ABSTRACT

BRAF gliomas have garnered significant attention in research due to the lack of effective treatments and their notable incidence, constituting 3% of all gliomas. This underlines the importance of investigating this area and the impact that targeted therapies could hold. This review discusses the development of targeted therapies for these tumors, examining the effectiveness of first-generation BRAF inhibitors such as Vemurafenib, Dabrafenib and Encorafenib, while addressing the challenges posed by paradoxical ERK activation. The advent of pan-RAF inhibitors, notably Tovorafenib, offers a promising advance, demonstrating enhanced efficacy and better penetration of the blood–brain barrier, without the issue of paradoxical activation. Nevertheless, continued research is essential to refine therapeutic strategies for BRAF-mutated gliomas, given the evolving nature of targeted therapy development.

1. Background

The annual incidence of brain tumors in the US population was 24.25/100000 person from 2014 to 2018. 29.1% of those are malignant tumors and 70.9% are non-malignant tumors. Gliomas account for 45% of pediatric brain tumors and 25.2% of adolescent and young adult brain tumors [1]. In 2016 and later on in 2021, the WHO classification of central nervous system tumors started including molecular classifications due to the high value of the molecular diagnosis in the sight of emerging novel targeted therapies [2]. Genetic mutations such as those in IDH, TERT promoter and 1p/19q are pivotal in tumor classification and influence therapeutic approaches in gliomas. IDH mutations are notably significant, predominantly found in lower-grade gliomas and secondary glioblastomas. These mutations occur early in tumorigenesis and are linked to better outcomes due to their roles in metabolic processes and DNA repair mechanisms. TERT promoter mutations are more common in primary glioblastomas and correlate with aggressive clinical behavior. The co-deletion of chromosome arms 1p and 19q, often observed in oligodendrogliomas, indicates a favorable response to combined chemotherapy and radiation [3]. BRAF-mutated gliomas accounts for approximately 3% of gliomas [4]. BRAF constitutes 1.5% of glioblastoma (GBM) mutations, and BRAF targeting has shown efficacy in brain tumors harboring BRAF mutations [5].

In the MAPK signaling pathway, BRAF is a specific variant within the RAF protein family found in mammals that plays a crucial role by activating the kinases MEK 1 and 2. These kinases, in turn, phosphorylate ERK 1 and 2. This phosphorylation process boosts the activity of transcription factors, leading to increased cell growth and a reduction in programmed cell death [6].

Importantly, BRAF inhibitors, especially first generation BRAF inhibitors such as Vemurafenib, Dabrafenib and Encorafenib, which are designed to target and inhibit BRAF kinase in cancer cells, can inadvertently cause the activation of the ERK signaling pathway. This happens when BRAF inhibitors induce dimerization of RAF proteins. Another paradoxical activation would happen in cells with RAS mutations or upstream receptor activation, where BRAF inhibitors bind to one part of the RAF dimer, which could also lead to the transactivation of the other RAF protein in the dimer. This process results in the unexpected activation of the downstream MEK-ERK pathway, which can promote tumor growth instead of suppressing it. The latter problem could be solved using pan-RAF inhibitors [7].

BRAF mutations can be segregated into three classes. Class I BRAF mutations, also known as BRAF V600 mutations, activate the MAPK pathway, with BRAF acting as a monomer. This activation is RAS-independent. Among all BRAF mutations, and consequently within this class, BRAF V600E is the most common mutation in cancer. Other mutations in this class include BRAF V600K/D/M/R. Classical BRAF inhibitors, like vemurafenib, are most potent in tumors harboring these mutations. Class II BRAF mutations are dimerization-dependent oncogenic mutations. This class includes mutations such as BRAF K601 mutations and BRAF L597 mutations. These mutations are insensitive to classical BRAF inhibitors. Finally, Class III BRAF mutations are RAS-dependent and dimerization-dependent mutations, generating low kinase activity. Examples of mutations belonging to this class are BRAF G466 mutations and the BRAF D287H mutation, to name a couple. This class is also insensitive to classical BRAF inhibitors [8,9]. BRAF fusions, such as the BRAF KIAA1549 mutation, belong to the second class of BRAF mutations [10].

Three main response assessment criteria are used in the context of brain tumors to determine whether CNS tumors are responding to treatment or not. Response Assessment in Neuro-Oncology for High-Grade Gliomas (RANO-HGG) criteria are specifically designed for high-grade gliomas (HGGs). Progression is defined as a 25% increase in contrast-enhancing area or significant enlargement of nonenhancing T2/FLAIR signal on MRI [11]. The RANO for Low-Grade Gliomas (RANO-LGG) were than added. They are tailored for low-grade gliomas (LGGs) and focus on T2/FLAIR measurements instead of contrast enhancement, as LGGs rarely enhance. They also take into account clinical outcomes which are significant in LGGs. The RANO-LGG criteria include minor response criteria characterized by a 25–50% decrease in T2/FLAIR tumor size. This acknowledges that responses in LGGs are often modest [12]. Later, in 2020, emerged the Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, they address the unique challenges in assessing responses in pediatric low-grade gliomas (pLGGs). These criteria consider the susceptibility of the developing brain to the toxic effects of tumors and treatments. The RAPNO criteria recommend combining imaging, clinical and sometimes functional evaluations. The criteria focus on T2 and T2-FLAIR sequences for assessing tumor changes and require postcontrast imaging for response evaluation [13].

It is important to highlight that for brain tumors, it was established that routine analysis of the BRAF V600E mutation should be conducted not only for well-known types like pleomorphic xanthoastrocytoma and ganglioglioma, but also for epithelioid glioblastomas, astrocytic tumors in individuals under 30 years of age and rhabdoid meningiomas. BRAF V600E immunostaining could be sufficient for screening purposes in glioblastomas and xanthoastrocytomas [14]. In fact epithelioid GBM has shown a good correlation between BRAFV600E mutation and BRAF VE1 immunohistochemistry thus IHC could be used for screening purposes [15]. Furthermore studies on mice showed that BRAF mutations in pediatric brain tumors increase epileptogenicity of the tumor and that BRAF inhibitors (BRAFi) decrease it. This shows that BRAFi could potentially have effects upon patient's symptoms and quality of life even in the absence of direct tumor size reduction [16]. This highlights the importance that should be given to the topic of BRAF mutated gliomas as clearly they are not a negligeable aspect of brain tumors and their treatment could have many positive outcomes.

Tovorafenib, also known as ‘DAY101’, ‘TAK-580’, ‘MLN2480’ is a new type II RAF inhibitor (a pan-RAF inhibitor) that was identified in a study that aimed to find an RAF inhibitor that would have an acceptable blood–brain barrier (BBB) penetrance and that is effective on both dimeric and monomeric forms of BRAF. The screening was conducted on human PLGA cells and murine models of PLGA. Tovorafenib showed efficacy on both BRAF^V600E mutations as well as KIAA1549:BRAF mutations, the latter being a fusion form of BRAF resulting in a dimeric BRAF oncoprotein. Other classical BRAF inhibitors showed little to no efficacy on KIAA1549:BRAF tumors. Furthermore Tovorafenib showed greater BBB penetrance than dabrafenib in normal brain tissue and did not display a paradoxical activation of ERK signaling [17]. Tovorafenib has also shown potency on BRAF and CRAF in vitro. It was most potent on CRAF isoforms but it was also potent on BRAF WT and V600E mutated BRAF [18]. Considering the fact that, at least since 2017, no single RAF inhibitor could inhibit C-Raf fusions in pediatric low grade gliomas [19], this constitutes a promising future for treatment of RAF-altered gliomas.

2. Pediatric low-grade gliomas

2.1. Vemurafenib

We found a lack of Phase II studies using Vemurafenib on pediatric patients with BRAF-mutated gliomas. Phase I trials were however available. In the NCT01748149 trial, a multicenter Phase I study for assessing the safety and tolerability of vemurafenib in 25 pediatric patients with relapsed brain tumors BRAF V600E mutation. The study was designed to assess the practicability of replacing whole tablets with crushed tablets in young children unable to swallow. 19 patients received whole vemurafenib tablets and six patients took crushed tablets twice daily. The results showed that the pharmacokinetic model, originally created for adult patients with BRAFV600E mutant melanoma, effectively forecasts pharmacokinetics in children and young adults when adjusted for body weight using allometric scaling. Furthermore in the crushed-tablet group, relative bioavailability was 96% (95% CI: 49–142%) compared with the whole tablets group [20] thus concluding that the use of vemurafenib crushed tablets with weight adjusted adult doses to treat pediatric patients with BRAFV600E mutated brain tumors was suitable. In another Phase I study, Nicolaides et al. included 19 pediatric patients with recurrent or progressive BRAFV600E brain tumors found that the recommended Phase II dose (RP2D) was 550 mg/m² [21]. Prior to both of these studies a retrospective study of six pediatric patients that used Vemurafenib at a target dose of 960–1100 mg/m²/day at 1 month of treatment (dose chosen arbitrarily by the researchers due to a lack of Phase I trial assessing the ideal dose to treat these patients) showed abnormally increased levels of low-density lipoproteins cholesterol (from 114 ± 14.1 mg/dl to 139.5 ± 51.5 mg/dl), total cholesterol (from 157 ± 29.7 mg/dl to 221.5 ± 42.1 mg/dl) and triglycerides (from 75.5 ± 24.9 mg/dl to 107.8 ± 44.4 mg/dl) with high-density lipoproteins cholesterol remaining normal 1 month after the beginning of treatment. The disruption of the blood lipids level remained present until last follow-up (44.6 ± 26.5 months) [22]. This could lead to long-term side effect that are not until now detected in larger clinical trials.

2.2. Dabrafenib with or without trametinib combination

The research done on the treatment of BRAF-mutated, LGGs in pediatric patients with dabrafenib was a lot richer than the research done to any other targeted therapy included in this review.

The NCT01677741 trial, a multicentered, Phase I/IIa trial evaluating the use dabrafenib in children and adolescent subjects, had two parts: the first part (n = 27, 15 of which had PLGGs) was to determine the Recommended Phase II dose (RP2D), and the second part (n = 17) was to assess the activity of dabrafenib. In the first part, a Phase I dose-escalating study was conducted on 27 pediatric patients with recurrent, refractory, or progressive BRAFV600-mutant solid tumors who had been treated with ≥1 prior therapy. Patients received oral dabrafenib to determine the RP2D. Dose limiting toxicity (DLT) was not experienced in any of the patients. All patients experienced at least one adverse event (AE), 59.3% had grade 3 or 4 AE. For pediatric patients aged >12 years, the dabrafenib RP2D was determined as 4.5 mg/kg/day, whereas for aged <12 years, the RP2D was 5.25 mg/kg/day [23]. For both parts, the objective response rate (ORR) was 44% (14 of 32, 95% CI: 26–62) and the progression free survival (PFS) was 35.0 months (12.9–not estimable). 29 patients (91%) had adverse events of any grade, and 9 had grade 3/4 AEs [24]. Similar results were displayed in the NCT02124772 trial, a four-part, Phase I/II, multicenter open-label study that was conducted to assess the safety, pharmacokinetics, pharmacodynamics and clinical activity of trametinib in pediatric patients with cancer or plexiform neurofibromas and trametinib with dabrafenib in pediatric patients with cancer Harboring V600 mutations. Among patients with BRAFV600 mutated pLGGs, a PFS of 16.4 months (95% CI: 3.2 to Not reported (NR)) was recorded in the trametinib monotherapy group (n = 13), a significantly higher PFS however was displayed in the trametinib in combination with dabrafenib group (n = 36) of 36.9 months (95% CI: 36.0 to NR). Likewise, the ORR was 15.4% (95% CI: 1.9 to 45.4) in trametinib monotherapy compared with 25% (95% CI: 12.1–42.2) in patients that were treated with the trametinib + dabrafenib combination [25]. Most recently, the NCT02684058 clinical trial, a Phase II multi-center, open-label trial including two cohorts, one of which included 110 pediatric patients with low grade gliomas harboring the BRAFV600 mutation. The combination of dabrafenib and trametinib was compared with standard chemotherapy. Of the 73 patients who received dabrafenib and trametinib, 47% had an overall response, whereas in the chemotherapy group, the ORR was 11% (4 of 37; 95% CI: 1.7 to 11.2). As for the PFS, patients receiving dabrafenib plus trametinib had a significantly longer PFS of 20.1 months (95% CI: 12.8 to not evaluable) compared with patients receiving chemotherapy where the PFS was 7.4 months (95% CI: 3.6 to 11.8). All the patients experience at least one AE, with a rate of grade 3 AE of 47% in the dabrafenib plus trametinib cohort compared with 94% of patients that received chemotherapy experiencing grade 3 AEs. It goes without saying that Dabrafenib is superior than chemotherapy in the treatment of this population [26].

However, Dabrafenib is not as potent on BRAF non-V600E mutated gliomas as it is on gliomas harboring BRAFV600E mutations. This has been displayed in a retrospective study was conducted on pediatric patients with low grade gliomas where off-label targeted therapies were administered, and their efficacy was assessed. Dabrafenib showed the best outcomes compared with the three other treatments (Vemurafenib, Trametinib and Everolimus). Vemurafenib and dabrafenib both showed a better 1 year PFS in patients with BRAF V600E mutated PLGGs of 93.8% (95% CI 63.2%–99.1%) compared with people harboring a BRAF fusion with a 1 year PFS of 53.3% (95% CI: 17.7–79.6%) [27].

2.3. Tovorafenib

As for Tovorafenib, a Phase II trial, the FIREFLY-1 (PNOC026) trial, investigated the efficacy of Tovorafenib in patients with BRAF-altered, relapsed/refractory pLGG. the study had two arms. Arm 1 (N = 77) contained patients with BRAF-altered PLGGs, Arm 2 (N = 60) however, broadened the spectrum by including RAF-altered PLGGs (including but not limited to BRAF). Until the date of publication, Arm 2 had only results for safety assessment and no results for efficacy in this arm was available. In arm 1, the ORR evaluated with RANO-HGG criteria (which was considered the primary outcome) was 67% (90% CI: 54–78). 69% (56–81) in patients with BRAF fusions and 50%(19–81) in patients with BRAFV600E mutations. However, the ORR assessed using the RAPNO criteria was lower at 51% and was the same between V600 BRAF harboring tumors and BRAF fusion tumors. The RANO-LGG criteria gave similar results with an ORR of 53% and similar between both subtypes of BRAF mutations. Regarding the PFS, with the RANO-HGG criteria, the median PFS was evaluated at 19.4 months. with the RAPNO criteria it was at 13.8 months and with the RANO-LGG criteria, it was estimated at 13.9 months. PFS was not reported distinctively for each population. Treatment-related AEs were seen in 98% of patients with a rate of grade 3 adverse events of 58% [28]. This trial based their treatment regimen on the doses for pediatric patients evaluated in a Phase I trial (NCT03429803) conducted on children with low grade gliomas using Tovorafenib, the treatment was dosed at 420 mg/m² once weekly with a maximal dose of 600 mg on days 1, 8, 15 and 22 of 28-d cycles [29]. The LOGGIC/FIREFLY-2 trial is the Phase III randomized open-label, multicenter, continuation trial to the Phase II trial above mentioned. 400 patients with pLGG harboring an activating RAF alteration who require first-line systemic therapy, were randomized in two arms; Arm 1 were patients will receive Tovorafenib as a monetherapy and Arm 2 in which patients will receive the investigator's choice of chemotherapy (either COG-V/C, SIOPe-LGG-V/C or VBL) [30]. The primary outcome measures are expected to be available by February 2026 [31] The US FDA decision of whether to approve or not Tovorafenib for the treatment of pediatric patients is scheduled for April 2024 as the new drug application was accepted [32].

3. Pediatric high-grade gliomas

The only trial available in the literature using BRAFi in pediatric high-grade gliomas was the NCT02684058 trial mentioned above. In this trial, the second cohort included 41 pediatric patients (aged 1–18) with BRAF V600-mutant high-grade glioma and with disease relapse or progression or lack of response to first-line therapy, received oral dabrafenib plus oral trametinib. All patients had previous therapy and grade 4 disease was diagnosed in 48.8% of them. The ORR per RANO criteria was 56.1% (95% CI: 39.7 to 71.5) with 12 (29.3%) complete response and 11 (26.8%) partial response. The median PFS was 9.0 months (95% CI: 5.3 to 24.0 months) for 24 patients. All patients had at least one adverse event, 68.3% experienced grade ≥3 events and 14 patients died [33].

4. Adults gliomas

4.1. Vemurafenib

In contrast to the lack of studies assessing vemurafenib as a potential treatment in pediatric gliomas, there is a richer literature regarding vemurafenib's effect on gliomas in adults. For example, in a Phase II VE-BASKET Study conducted on 24 patients with a median age of 32 years who had gliomas harboring BRAF V600 mutations, including 11 with malignant diffuse glioma, 7 with PXA, 2 with PA, 3 with AGG and 1 high-grade glioma not otherwise specified assessed the efficacy of vemurafenib. The confirmed ORR was 25% (95% CI: 10–47%) and median progression-free survival was 5.5 months (95% CI: 3.7–9.6 months). Additionally, 20% of patients had adverse events including 13% grade 3 and 4 events [34]. Similar results were displayed in a pan-cancer study including gliomas, where vemurafenib was used on patients with BRAFV600-mutated tumors [35]. In the ACSE basket study, Vemurafenib was assessed in adults with BRAFV600E cancers. The ORR in patients with gangliogliomas was 66.7% (95% CI: 28.4–94.7) with only four patients in this group. As for Xanthastrocytoma, the ORR was 50% (95% CI: 14.7–85.3) also with only four patients. And finally, 10 patients with glioblastoma showed a lower ORR of 33.3% (95% CI: 10.9–61.0). this was expected because of glioblastoma's higher malignancy [36]. Finally, a Phase I study assessing Vemurafenib in combination with Everolimus – a mammalian target of rapamycin (mTOR) inhibitor – on 20 patients with BRAF mutated advanced solid tumor. The rationale behind this was to counteract resistance to BRAF inhibitors by blocking alternative cancer growth pathways such as the mTOR pathway. This combination showed a partial response in optic nerve gliomas [37].

4.2. Dabrafenib

The evaluation of dabrafenib in adults with gliomas has been conducted in two studies to our knowledge. The first being the ROAR trial; a multicenter, open-label, single-arm Phase II study, including 206 adults with BRAF V600E mutated cancers. 45 patients were assigned to the high-grade glioma cohort and 13 to the low-grade glioma cohort. Patients received oral dabrafenib and oral trametinib.

In the high-grade glioma cohort, the ORR was 31% (95% CI: 18–47) and the median PFS was 4.5 months (1.8–7.4); As for the low-grade cohort, the ORR was 69% (95% CI 39–91) (one complete response, six partial and two minor responses) and the median progression-free survival was 14 months (4.7–46.9). 54 patients of 58 (93%) had adverse events: 47% in the high-grade glioma cohort and 61% in the low-grade glioma cohort. 53% experienced grade 3 and 4 events. 58% of high-grade glioma patients died whereas four died in the low-grade glioma cohort [38]. This publication is part of a bigger trial assessing the effect of dabrafenib and trametinib in patient with BRAFV600E mutated rare cancers [39]. Furthermore, a retrospective cohort conducted in the databases of six neuro-oncology departments identified 28 adults with recurrent or disseminated high-grade gliomas harboring the BRAFV600E mutation. Patients were previously treated with RAFi and MEKi. 11 of them received vemurafenib in monotherapy, two received dabrafenib in monotherapy, five received Vemurafenib in combination with Cobimetinib and ten received Dabrafenib with Trametinib. According to the RANO-HGG criteria, the ORR in all the patients was 39% and among the patient who achieved an objective response the median PFS was 18 months, however the PFS was lower (9 months) in patients with stable disease and even lower in patients with a progressive disease (2 months). The treatment relative ORR and PFS were not reported [40].

4.3. Tovorafenib

Tovorafenib on adults in the context of gliomas has only been only tried in the NCT01425008 Phase I study that was conducted to evaluate the safety of Tovorafenib treatment in humans as well and to assess the anti-tumor activity of Tovorafenib ultimately to determine a treatment regimen to be recommended in Phase II trials and future studies. The study had two phase, the first being a dose escalation phase conducted only on adults (age >18) with solid tumors and the second being a dose expansion phase that was conducted on adults with solid tumors as well as adults with locally advanced, metastatic and/or unresectable melanomas. The drug-related adverse events occurred in 86% (22% > grade 3) of patients in the dose escalation phase and 90% (38% > grade 3) in the dose expansion phase. The safety was deemed acceptable by the researchers. As for the tumor response, it was considered promising with the highest ORR (50%) occurring in treatment naive BRAF-mutated tumors who received the treatment once every other day at the recommended Phase II dose of this regimen (200 mg) [41].

5. Discussion

5.1. Tovorafenib or dabrafenib in the treatment of pediatric low-grade gliomas?

According to the most relevant data gathered (summarized in Table 1), we can deduce that in pediatric patients, there are not enough reliable data to assess whether Vemurafenib could have a significant role in the treatment of PLGGs. The two treatments that should be addressed and compared however are the dabrafenib and trametinib combination and the Tovorafenib monotherapy. As exposed previously Tovorafenib and the Dabrafenib and trametinib combination displayed similar ORR when both using the RANO-LGG criteria (47% with the dabrafenib and trametinib combination versus 53% with Tovorafenib). However, the PFS in BRAFV600E patient was better with the combination therapy compared with the Tovorafenib monotherapy (20 vs 13). This suggests that in the context of BRAFV600E mutated PLGGs, the combination of dabrafenib and trametinib is to prefer over the Tovorafenib monotherapy. Nevertheless, long term results could change this premise, especially knowing that Tovorafenib being a pan RAF inhibitor has a lower chance of emerging resistance due to transactivation of other RAF proteins than BRAF, as discussed in the introduction [7].

Table 1.

Phase II studies assessing the efficacy and safety of RAFi in patients with RAF-mutated gliomas.

Trial	Treatment regimen	Population treated	N	Overall response rate†	Progression free survival†	Grade 3 or 4 adverse events	Ref.
NCT02124772	Dabrafenib + Trametinib	BRAF V600 mutated pLGGs	36	25%	36.9 months	N/A	[24]
NCT02684058	Dabrafenib + Trametinib	BRAF V600 mutated pLGGs	73	47%	20.1 months	47%	[25]
FIREFLY-1 (PNOC026)	Tovorafenib	BRAF-altered PLGGs	77	51%	13.8 months	63%	[27]
		RAF-Altered pLGGs	60	N/A	N/A
NCT02684058	Dabrafenib + Trametinib	BRAF V600 mutated pHGGs	41	56.1%	9.0 months	68.3%	[32]
VE-BASKET	Vemurafenib	BRAF V600 mutated gliomas	24	25%	5.5 months	13%	[33]
ACSE basket	Vemurafenib	Adults with BRAF V600E Ganglioglioma	4	66.7%	N/A	N/A	[35]
		Adults with BRAF V600E Xanthastrocytoma	4	50%	N/A	N/A
		Adults with BRAF V600E Glioblastoma	10	33.3%	N/A	N/A
ROAR trial	Dabrafenib + Trametinib	Adults with BRAFV600E LGG	13	31%	4.5 months	53%	[37]
		Adults with BRAFV600E HGG	45	69%	14 months

^†The ORR and PFS displayed are according to the RANO criteria suitable for the patient population or else the only measurement available in the study.

N: Number of patient treated; ORR: Objective response rate; PFS: Progression free survival; pLGGs: Pediatric low-grade gliomas.

According to the data gathered, it is safe to assume that Tovorafenib monotherapy is however a better choice for BRAF fusion mutations as it has displayed a better effect on KIAA1549:BRAF tumors compared with first generation BRAFi [17]. In fact first generation BRAF inhibitors like vemurafenib may not be suitable for treating pediatric astrocytomas with KIAA1549-BRAF fusion as a single therapy option. Their use could even be inadvisable for these types of tumors [42]. There is however a lack of studies assessing the efficacy of the dabrafenib and trametinib combination in BRAF non-V600 mutated PLGGs [43], thus, while unlikely, this combination could still display promising results in this population in future studies. Also, Tovorafenib could be a better option for RAF-altered gliomas in general excluding the BRAFV600 mutation. This is because Tovorafenib, as discussed before, has had effects on CRAF even more potently than on BRAF. It is nevertheless important to note that those results were results of experiments conducted in vitro and to extrapolate them onto humans is research-needing subject. The mechanism of actions of dabrafenib and trametinib on one hand and Tovorafenib on the other hand, along with the mechanism of resistance, are illustrated in Figure 1.

Figure 1.

BRAF mutations and BRAF inhibitors action mechanisms and resistance mechanisms. (1) BRAFV600 activation of MAPK pathway in an RAS independent way and as a monomer. (2) Dabrafenib inhibiting BRAF and thus cell proliferation. (3) Resistance mechanism to dabrafenib monotherapy involving CRAF and BRAF dimerization. (4) Combination of Dabrafenib and Trametinib way of evading the resistance mechanism. (5) Tovorafenib action mechanism on BRAFV600 mutation after dimerization with CRAF. (6) BRAF KIAA:1549 mutation mechanism in cell proliferation. (7) failure of dabrafenib to inhibit BRAF dimer. (8) Tovorafenib inhibition of BRAF KIAA:1549 thus inhibiting cell proliferation.

As a final note, although the brain distribution of Tovorafenib was significantly better than dabrafenib and Encorafenib and vemurafenib [44], a murine study tested a transformation of dabrafenib that reduce the molecular weight of the molecule thus evading the P-glycoprotein efflux mechanism that normally impedes the blood–brain barrier penetrance of relatively low molecular weight molecules. The new molecule was named Everafenib. Everafenib have shown an increased brain–blood barrier penetrance compared with dabrafenib in mouse models of brain melanoma metastases. This method could further increase the effects of first generation BRAFi on brain tumors [45].

5.2. Encorafenib & binimetinib potential

When discussing BRAFi in combination with MEKi, it is impossible to not mention the Encorafenib and Binimetinib, as it is the gold standard treatment in BRAF mutated metastatic melanomas [46]. This combination has also shown it's efficacy in non-small cell lung cancers (NSCLCs), as it has displayed the best outcomes out of all other BRAFi [47]. The Encorafenib and Binimetinib combination has been tried on patient with BRAFV600 mutated gliomas (NCT03973918), the initial estimated primary completion of this trial is in July 2025 [48]. Unfortunately, this trial has been terminated early due to the COVID-19 pandemic, results of this trial are promising, but the available published data concerns a small sample size (n = 5), thus no conclusion can be yet drawn from this trial [49].

5.3. Tovorafenib in other cancers

Tovorafenib have shown its efficacy in other type of cancers. In the case of a 5-year-old child with an advanced spindle cell carcinoma that harbored a novel oncogenic fusion SNX8-BRAF, Tovorafenib displayed the ability to stabilize the disease progression after the tumor developed resistance to MEKi trametinib [50]. Furthermore, in an in vitro study on multiple myeloma cells, Tovorafenib have shown potency in a monotherapy compared with dabrafenib [51]. This highlights the potential use of Tovorafenib in types of cancer that it was not initially designed for.

5.4. Adults & high-grade gliomas

When considering adult gliomas, the research on vemurafenib, although richer than in the pediatric population, is still scarce and not completely adequate to assess the efficacy of this treatment. However, the data points toward dabrafenib being the better option in adult patients with BRAF-altered gliomas as it has displayed similar ORR (31%) and PFS (4.5 months) in patients with high grade gliomas to the ORR (25%) and PFS (5.5 months) of vemurafenib in patients that were mixed between high and low grade gliomas, dabrafenib showing way better outcomes (ORR: 69%, PFS: 14 months) on low grade gliomas in adults [35,39].

5.5. Other RAF inhibitors

On one hand, Sorafenib, a multikinase inhibitor was tested on pediatric patients with LGGs. The results were paradoxically in favor of the disease's progression. The median PFS was 2.8 months, most patients had disease progression. Sorafenib was deemed to maybe even promote tumor growth [52]. On the other hand Regorafenib, also a multikinase inhibitor that is considered to have an effect on BRAF, has shown efficacy in recurrent glioblastoma [53], that is, with the expression of one of five biomarkers, none being related to BRAF and further research is needed to confirm those results [54].

5.6. Other management options

Management of pediatric gliomas presents itself as a challenge for the clinician with numerous obstacles to overcome. Apart from the innovative use of targeted therapy, the treatment of these tumors relies on the three pillars of surgery, radiotherapy and chemotherapy. Observation can also be a potential option for asymptomatic, incidentally discovered low grade gliomas. Gross total resection in the case of such tumors can provide survival benefits and possibly long-term tumor latency without use of subsequent therapies [55,56]. In the case of tumor recurrence, additional surgery, radiotherapy or chemotherapy can be beneficial. However, the current trends favor the use of radiotherapy for older patients with pediatric LGGs or in the case of relapse after surgery, chemotherapy or targeted drugs [57]. The rationale behind this indication is based on the potential long-term adverse events of radiotherapy such as cognitive impairment, secondary neoplasms and endocrine disease [58,59].

In comparison to LGGs, observation in asymptomatic cases has no place in the management of pediatric-high grade gliomas. Similarly, high-grade tumors are also treated by possible combinations of surgery, radiotherapy and chemotherapy with the adoption of novel agents such as targeted drugs and immunotherapy [60]. Nevertheless, surgery remains the leading indicator for prognosis and overall survival for patients. Although radiotherapy is beneficial in inoperable cases, it can also be utilized as an adjuvant treatment option in order to diminish residual tumor tissue. Chemotherapy drugs such as temozolomide are also usually prescribed in the adjuvant setting [60].

6. Conclusion

In conclusion, the management of BRAF-mutated gliomas has significantly evolved in recent years. This review provides a comprehensive overview of the existing strategies for management of BRAF gliomas; Tovorafenib stands out for its superior efficacy in treating pediatric LGGs with BRAF fusions, suggesting it should be the standard monotherapy for these patients. For pediatric patients with low-grade or high-grade gliomas featuring the BRAV600E mutation, a regimen combining Dabrafenib and Trametinib has proven to be the most effective treatment option. However, this area warrants further exploration due to the current scarcity of research on high-grade gliomas in the pediatric population. For adults over 18, the combination of Dabrafenib and Trametinib remains the preferred treatment option, given the absence of better alternatives. Nonetheless, the potential benefits of Tovorafenib for this age group suggest that Phase II trials are justified to assess its efficacy further (Figure 2).

Figure 2.

Summary diagram for the management of patient with RAF-mutated recurrent or disseminated glioma.

7. Future perspective

Research should be done to confirm or deny the efficacy of tovorafenib in high grade gliomas and adult gliomas. other treatment options should resurge and make themselves available for populations experiencing resistance to treatment, and example of that would be the new molecule Everafenib that could constitute a promising alternative for Tovorafenib.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.