Point/counterpoint: Upfront BRAF inhibition for adult BRAF-mutant high-grade gliomas

Gliomas classified as CNS WHO grade 3 and 4 (herein referred to as HGG) are aggressive, fast-growing tumors with a poor prognosis and limited therapeutic options.1 Given their rapid progression, there is a critical clinical need for immediate adjuvant treatment following surgery. For decades, focal radiation therapy, with or without chemotherapy, has been the standard of care for patients with these tumors, though its effectiveness varies.2 Recent advances in molecular profiling have identified distinct subtypes of HGG with specific genetic alterations.3 Testing for BRAF and IDH alterations currently holds the greatest clinical significance in gliomas based on the identification of clinically relevant targetable alterations.4 The BRAFV600E mutation, which is classified as ESCAT evidence tier I according to the ESMO Scale for Clinical Actionability of Molecular Targets,4 is detectable by most sequencing panels. In addition, BRAF alterations are considered as characteristic features of several glioma subtypes in the 2021 WHO Classification of Tumors of the Central Nervous System and should therefore be routinely assessed.1 The BRAFV600E mutation is more commonly found in pediatric low-grade gliomas, but also occurs in older adolescent and adult patients.5 The exact incidence of BRAF alterations in HGG remains under study, but large datasets estimate the percentage to be around 3–5% in adult patients.3,6 However, the prevalence of this mutation varies by tumor type, with reported frequencies of 69% in epithelioid glioblastoma, 38% in anaplastic pleomorphic xanthoastrocytoma (aPXA), and 46% in anaplastic ganglioglioma.5 While BRAFV600E is considered a driver mutation in pediatric gliomas, which typically harbor few additional alterations, adult gliomas often exhibit activation of other pathways, and BRAFV600E may represent a bystander mutation in some of these cases. The development of targeted therapies, including BRAF and MEK inhibitors, has introduced promising new treatment options for these difficult-to-treat tumors with BRAFV600E mutation. Based on the efficacy of BRAF inhibition in other cancers harboring the BRAFV600E mutation, such as melanoma,7 BRAF inhibitors (BRAFi) have begun to be utilized for the treatment of HGGs since the early 2010s.8 A recent publication highlights the use of neoadjuvant and pre-radiation chemotherapy (PRC) across cancer types, in contrast to its relative paucity in GBM specifically.9 Despite the available data on the effectiveness of both standard treatments (radiation therapy and chemotherapy) and targeted therapies, such as BRAF and MEK inhibitors, for HGGs, there is ongoing debate regarding the optimal treatment strategy. Specifically, the question remains whether targeted therapy should be used in the upfront setting (following or in lieu of radiation therapy) or be reserved for recurrence. Several pediatric and adult case reports have demonstrated the efficacy of BRAFi, either as monotherapy or in combination with MEK inhibitors (MEKi), in patients who failed standard treatments involving radiation and chemotherapy.10 Some cases reported remarkable radiographic and clinical improvements. In 2022, Arbour et al. reviewed published cases of HGG with BRAFV600E mutations treated with BRAFi with or without MEKi.10 They identified 32 patients with a median age of 22.5 years (range: 1.5–50 years). Best responses were reported in 31 patients, including 4 complete responses (CR) (13%), 23 partial responses (PR) (74%), 2 cases of stable disease (SD) (7%), and 2 cases of progressive disease (PD) (7%). The most comprehensive compilation of treatment cases to date is a systematic review analyzing the prevalence of BRAFV600 mutations in gliomas and responses to BRAFi treatment from case reports and clinical trials.11 Among 394 BRAFV600-mutant gliomas treated with BRAFi from 130 publications, 97 adult HGG cases showed CR, PR, SD, and PD in 6 (6%), 31 (32%), 27 (28%), and 33 (34%) patients, respectively. This was similar to the 25 pediatric HGG cases when accounting for cohort size, which showed CR, PR, SD, and PD in 4 (16%), 10 (40%), 4 (16%), and 7 (28%) patients, respectively. Additionally, larger, retrospective series have demonstrated the efficacy of BRAF-targeted therapy in recurrent HGG. A bi-institutional cohort of 10 adults with relapsed HGG (4 glioblastoma, 6 aPXA) revealed 50% of patients (n = 5) with clinical benefit for at least four months, and 40% remained on therapy for 20 months or longer.12 This is similar to what has been reported in a separate cohort of 11 heavily pretreated pediatric patients (6 glioblastoma, 2 anaplastic ganglioglioma, 2 aPXA, and 1 anaplastic astrocytoma).13 Though detailed treatment courses were not provided, all patients had prior radiation therapy, and 9 received systemic therapy. Four patients (36%) responded, including 1 CR and 3 PR. There are no data for first-line treatment with targeted therapy in the adult HGG population. Drawing from the pediatric experience, a series of 19 pediatric HGG patients with BRAFV600E mutations were treated with targeted therapy in the first-line setting.14 The vast majority (n = 16, 84%) received upfront radiation therapy followed by BRAFi ± MEKi, while three underwent biopsy with upfront targeted therapy alone. The overall response rate (ORR) was 64%, with CR and PR observed, and only one case of PD. Their study demonstrated an 18-month progression-free survival (PFS) of 83% compared to 42% in a historical BRAF-mutant cohort, and a 3-year overall survival (OS) of 82% versus 44% in the same cohort. Four studies, including two in adults, have demonstrated the efficacy of BRAFi ± MEKi for gliomas with BRAFV600E mutations. While a randomized trial for first-line treatment of pediatric low-grade gliomas demonstrated that the combination of BRAFi and MEKi was superior to standard chemotherapy,15 no similar randomized studies exist for patients with HGG. Uncontrolled open-label trials have demonstrated the efficacy of BRAFi. Hargrave et al. investigated dabrafenib and trametinib in pediatric HGG with BRAFV600E mutations.16 Patients received at least one prior treatment (radiation and/or chemotherapy) before targeted therapy. The ORR was 56%, with a higher response rate (67%) in grade 3 PXA. Most responses occurred within 4 months by independent assessment. Treatment was well-tolerated, with only one patient discontinuing treatment due to adverse effects. Dose reductions were required in 32% (dabrafenib) and 17% (trametinib) of cases. The 12-month PFS was 44%, and OS was 33%. In adults, the VE-Basket trial evaluated vemurafenib in 24 patients with BRAFV600E mutation-positive gliomas of all grades, including 11 malignant diffuse glioma (six glioblastoma and five anaplastic astrocytoma), 7 PXA, three anaplastic ganglioglioma, two pilocytic astrocytoma, and one high-grade glioma, not otherwise specified.17 The ORR was 25% (42% for PXA, 9% for malignant diffuse gliomas). For the entire cohort, they reported an ORR of 25% including CR; PR; SD; PD in 1 (4%); 5 (21%), 10 (42%); and 5 (21%), respectively. The confirmed clinical benefit was 38%. The median PFS was 5.5 months with a median OS for all patients was 28.2 months. The ORR was higher with PXA (42%), and median OS was not reached. Ten patients required one or more vemurafenib dose reductions, and only one discontinued treatment as a result of intolerable adverse effects. Similarly, the ROAR study investigated dabrafenib and trametinib in 45 adult HGG patients (31 glioblastoma (69%), 5 PXA grade 3 (11%), 5 anaplastic astrocytoma (11%), 1 anaplastic ganglioglioma (2%), 1 anaplastic oligodendroglioma (2%), 1 astroblastoma (2%), and 1 undifferentiated (2%)).18 All except one received prior radiation therapy, and all but three received at least one line of prior chemotherapy. The ORR was 33% (3 CR, 12 PR), with stable disease in 22% and PD in 42%. Median duration of investigator-assessed response was 36.9 months and 13.6 months by independent radiology review. The median OS of 17.6 months for the entire HGG cohort (13.7 months for glioblastoma and 45.2 months for other HGG subtypes). Adverse events led to dose reductions in 22 (38%) patients, interruptions in 24 (41%) patients, and permanent discontinuation in five (9%) patients (three in the HGG cohort [headache, decreased ejection fraction, and cardiac conduction disorder]). Recently, a small, prematurely terminated phase 2 study evaluated encorafenib and binimetinib in 5 adults with HGG (1 glioblastoma, 4 PXA grade 3).19 All had received prior radiation and had one or more recurrences (up to five). The ORR was 80% (2 CR, 2 PR), with a median PFS of 9.4 months and median OS of 14.6 months in the entire cohort. Adverse events led to treatment discontinuation in one patient (20%, cilioretinal artery occlusion), and one patient had a dose reduction for grade 4 elevated creatine phosphokinase (CPK). Table 1 provides an overview on trials, retrospective studies, and case reports. Studies and Case Reports on BRAFV600E-mutant Gliomas Treated with BRAF Inhibitors Abbreviations: CR = complete response; HGG = high-grade glioma; ORR = overall response rate; PD = progressive disease; PR = partial response; PXA = pleomorphic xanthoastrocytoma; SD = stable disease. Studies and Case Reports on BRAFV600E-mutant Gliomas Treated with BRAF Inhibitors Abbreviations: CR = complete response; HGG = high-grade glioma; ORR = overall response rate; PD = progressive disease; PR = partial response; PXA = pleomorphic xanthoastrocytoma; SD = stable disease. Ongoing trials are not listed above and include the Phase 1/2a study of plixorafenib in BRAFV600E altered tumors, currently enrolling recurrent primary CNS tumors (NCT02428712). In addition, for the purposes of this review, we did not include studies that only enrolled patients with pediatric LGG. One such study worth highlighting is the Phase 2 FIREFLY-1 trial (PNOC026; NCT04775485), which showed rapid and clinically meaningful responses to tovorafenib, a type II RAF inhibitor, in pediatric patients and adolescent and young adults with recurrent pLGG.20 While the studies summarized above indicate encouraging responses to BRAFi in both children and adults, they are limited by small sample sizes. In addition, the above studies were conducted in patients with recurrent disease, and no study has directly compared upfront BRAFi to the standard of care in adult patients with HGG, making it unclear whether BRAFi should be used in the upfront setting. In this context, we outline key arguments both for and against upfront BRAFi in HGG, with the aim of informing future research, clinical trial design, and clinical practice. While encouraging responses to BRAF inhibitors in HGG have been reported in single-arm phase 2 basket studies by the Adult Brain Tumor Consortium,19 the VE-Basket trial17 and the ROAR trial,18 these included only recurrent glioma patients. It should be noted that the response rate in recurrent HGG is much lower than in CNS WHO grade 2 gliomas—9–80% based on the studies summarized in Table 1. The duration of response is also shorter, 3.8–9.4 months, albeit in recurrent HGG. It is possible that a fraction of patients with newly diagnosed HGG, particularly older adults, will be insensitive to BRAF-targeted therapy.18 However, based on the treatment-refractory nature of HGG, the potential disease-shrinking benefit of targeted therapy, and the overall high tolerability of targeted therapy, we believe consideration of BRAF targeted therapy in the first line is warranted for carefully selected newly diagnosed HGG patients, in particular younger patients. Specifically for patients with non-glioblastoma HGG, radiation therapy could be delayed or omitted in certain cases in favor of treatment with upfront BRAFi. This strategy is particularly appealing both in patients where radiation poses a higher risk for toxicity (eg, large tumors, leptomeningeal disease) or, conversely in cases where HGG is less aggressive (eg, gross total resection). Given the rapid response to BRAFi plus MEKi (typically within three to six months), treatment efficacy can be assessed early, and regularly, with the option of salvage radiation, re-resection, or systemic chemotherapy in the event of clinical or radiographic progression. The argument to delay radiation applies particularly to grade 3 PXA, which may have a more favorable prognosis than other HGG subtypes and is also more prone to leptomeningeal dissemination, favoring BRAF-targeted therapy. These complex decisions should be discussed in multidisciplinary tumor boards and involve comprehensive patient and family discussions. The safety of BRAFi in combination with or following radiation therapy needs to be better elucidated. On one hand, in highly symptomatic patients with significant tumor burden, rapid initiation of BRAFi and MEKi (before or with concurrent radiation therapy), could help to control disease symptoms. On the other, prior reports suggested increased cutaneous toxicity when combining BRAFi or MEKi with radiation. While the risk may be tolerable and small relative to the overall risks of treatment, it warrants consideration.21 Safety of adjuvant BRAFi following radiation is currently being evaluated, along with efficacy, in a clinical trial (NCT03919071), including pediatric, adolescent, and young adult patients. It is recognized that the adolescent and young adult population (age, 15–39 years) encompass adult and pediatric type gliomas.22 In this population, the incidence of BRAFV600E mutation-positive gliomas is higher than in older adults and may reflect distinct tumor types and prognosis. Retrospective data suggest that patients 18–35 with glioblastoma carrying a BRAF alteration have significantly improved overall survival compared to older patients.12 In the ROAR trial, 96% of the HGG patients were in the 18-65 age group, and patients aged 18 to < 40 years had a higher response rate compared to patients ≥ 40 (ORR: 41% vs 17%).18 In this population, where survivorship may be prolonged, and where toxicities of chemotherapy and radiation need to be minimized, upfront BRAFi may represent an effective and quality-of-life enhancing approach to achieve control of their disease.23 Long-term toxicity may influence treatment duration, and an indefinite course can be psychologically distressing or impact family planning for some patients. Upfront discussion of these considerations should be included when initiating first-line targeted therapy. A significant subset of adult HGG patients with BRAFV600E mutation receive a histological diagnosis of glioblastoma, and currently, regardless of age, have a dismal prognosis. In large retrospective cohorts, the presence of a BRAFV600E alteration did not intrinsically confer an improved outcome in the setting of standard chemo-radiation and prior to the adoption of BRAF-inhibition.12 Methylation of the O6-methylguanine-DNA methyltransferase promoter (MGMT) in glioblastoma has been associated with a clinical benefit from the current standard of care with the Stupp protocol. However, this addition of adjuvant temozolomide in the setting of MGMT-unmethylated glioblastoma, which represents 55–60% of all glioblastoma may not confer any additional benefit,24,25 and clinical trial options are often sought for these patients. As such, the case could be made to incorporate BRAF-targeted therapy into the first-line setting for a subset of MGMT-unmethylated HGG. Based on the treatment-refractory nature of HGG, the potential disease-shrinking benefit of targeted therapy, and the overall high tolerability of targeted therapy, we believe that BRAF targeted therapy in the first line could be an effective strategy in carefully selected patients, and that future trials should explore this strategy. Specifically, incorporating BRAF targeted therapy in the first line with radiation for MGMT unmethylated glioblastoma needs to be considered as an alternative to adjuvant chemotherapy. First-line BRAF targeted therapy in place of radiation may also be a reasonable option for non-glioblastoma HGGs that carry a better prognosis, are younger at diagnosis, and may benefit from delaying radiation. The duration of BRAFi/MEKi combination therapy following radiation therapy is subject to debate and warrants further investigation. Discussion of upfront treatment with BRAFi needs to include the potential burden of toxicity/adverse events and the need for daily medication compliance. Common adverse effects include dermatologic reactions (rash, photosensitivity, pruritus), gastrointestinal symptoms (diarrhea, nausea), and systemic effects such as fatigue and fever, particularly with combination therapy.7,18,26 Serious complications require close monitoring. Cardiotoxicity, including left ventricular dysfunction, is linked to BRAFi and MEKi.27 Venous thromboembolism, particularly deep vein thrombosis and pulmonary embolism, is another significant risk.28 Ocular toxicity, such as retinal vein occlusion, and paradoxical squamous cell carcinomas due to MAPK further toxicities with more inhibitors, such as the type II RAF elevated and plixorafenib will also need to be assessed in One of the most significant associated with BRAF particularly when it is used as an upfront treatment, is the potential for the development of at any of treatment from initiation to in the treatment The ROAR study showed an ORR of ≥ 50% across all cohorts, but only an ORR of in BRAFV600E mutation-positive HGG. The decreased response of BRAFi in the HGG cohort is to be to the that BRAF mutations are not the primary of some high-grade tumors, but and the that BRAF tumor of a patient and/or within a tumor This is by the presence of other mutations that may to the in BRAF mutation-positive genetic alterations (eg, a in a high burden, the of of or and are often found BRAF in high-grade gliomas that and much more than in low-grade gliomas, in a limited duration of benefit from targeted therapy. It is unclear whether treatment in the first-line setting the benefit or to at the same of therapeutic benefit have been including elevated of the or mutations in or of activation of the of and activation of including and BRAF inhibitors are utilized in the upfront this may result in in initiating such as radiation and chemotherapy, BRAF been to be effective in PFS and OS for most patients with newly diagnosed For studies have that delaying radiation therapy can overall survival in patients with in the of clinical trial evidence that that BRAF inhibitors are effective in and in the of some clinical trials that of patients with HGG can BRAF delaying radiation therapy to trial BRAF inhibition in the upfront setting is particularly the potential with radiation therapy in favor of BRAF inhibition first may be considered for most patients with HGG. of patients with BRAF-mutant glioblastoma responses to BRAF the of these responses is In the ROAR trial, PFS was only that disease In addition to the clinical BRAFi in the upfront setting for HGG, there are several the and of BRAFi at the of diagnosis as a therapy. evidence these as a first-line treatment, it is highly that may to the of these when is the burden associated with these could BRAFi, when with MEKi, are with often use this to This of and It is possible that patients of lower and other may not have to or be to this treatment in an compared to and chemotherapy, these critical the efficacy, and of care with BRAF inhibition in the upfront particularly when the of BRAF inhibitors In the of we BRAF inhibition to be reserved for the setting of more data can be from clinical trials specific to HGG in A question is whether upfront BRAFi should or standard therapy. studies suggest of upfront BRAFi HGG are more aggressive in Given their distinct clinical most pediatric have targeted as of the upfront treatment for both and high-grade gliomas, adult have this strategy with more often further clinical trials whether BRAFi should be used before or particularly in MGMT-unmethylated Additionally, of BRAFi with radiation and/or could be further the efficacy of BRAFi, with tumors alternative survival should explore combination such as BRAFi/MEKi with inhibitors, inhibitors, or and combination with other may also help all BRAF-mutant HGGs to targeted therapy, highlighting the need for better patient mutations in and promoter may impact therapeutic which patients benefit most from upfront BRAFi versus standard therapy will be critical for Most evidence for BRAF inhibition from pediatric studies, but these to adults is due to in tumor patients often receive BRAFi treatment, while the of therapy in adults remains These and their need to be further elucidated. trials be the approach to the efficacy of upfront BRAFi. 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