Product information and disease description Place of product in therapy Approaches to treatment Current treatment options and standard of care

RAF and MEK inhibitors

19 evidence topics · 20 sources

Dabrafenib plus trametinib versus carboplatin plus vincristine as first-line therapy in BRAF V600 pLGG

“A total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001).” (opens the source at this quote in a new tab)
“The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy.” (opens the source at this quote in a new tab)

FDA approval of dabrafenib plus trametinib for BRAF V600E pLGG

“On March 16, 2023, the U.S. Food and Drug Administration (FDA) approved dabrafenib in combination with trametinib (Tafinlar®, Mekinist®, Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy.” (opens the source at this quote in a new tab)
“This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAF V600E mutation.” (opens the source at this quote in a new tab)

Canadian consensus: upfront BRAF inhibitor with or without MEK inhibitor for BRAF V600E gliomas

“We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean.” (opens the source at this quote in a new tab)
“Our group felt that, given the fact that some questions remain regarding the duration of treatment with targeted therapy and outcome at discontinuation, chemotherapy should not be removed from the treatment options and that a thorough discussion with the family is crucial.” (opens the source at this quote in a new tab)
“Based on clinical experience and consensus, we currently suggest treating with BRAFi ± MEKi for a total of 36 months for PLGG and 60 months for HGG.” (opens the source at this quote in a new tab)

European standard clinical practice: targeted therapy in the first line

“Currently, targeted therapy as first line therapy for paediatric low grade gliomas is only acceptable in the context of clinical trials. Taking into consideration recently published data, possible benefits of targeted therapy could however be discussed for BRAFV600E mutant LGG” (opens the source at this quote in a new tab)

Brazilian consensus: therapeutic recommendations for BRAF-altered LGG

“LGG8 | For low-grade gliomas with BRAF V600 mutations, inoperable or with residual lesion, or refractory/relapsed, consider combination therapy with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor).” (opens the source at this quote in a new tab)
“LGG9 | For low-grade gliomas with KIAA1549-BRAF fusion or wild-type BRAF, DO NOT use type 1 BRAF inhibitors (such as dabrafenib or vemurafenib).” (opens the source at this quote in a new tab)
“LGG10 | For patients with low-grade gliomas that present with the KIAA1549-BRAF fusion, consider using tovorafenib as a therapeutic option.” (opens the source at this quote in a new tab)
“Level of Agreement: 85%.” (opens the source at this quote in a new tab)
“Importantly, the panel recommended against the use of type I BRAF inhibitors (such as dabrafenib or vemurafenib) when a KIAA1549-BRAF fusion is detected, due to the risk of paradoxical MAPK pathway activation and subsequent tumor progression.25 For these patients, tovorafenib may represent an alternative.” (opens the source at this quote in a new tab)

NCCN Guidelines for Pediatric Central Nervous System Cancers: scope

“The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents.” (opens the source at this quote in a new tab)

Selumetinib in recurrent or progressive pLGG: PBTC-029 phase 2 trial

“On stratum 1, 9/25 (36%) patients achieved a partial response (PR).” (opens the source at this quote in a new tab)
“On stratum 3, 10/25 (40%) patients achieved a PR with a median follow-up of 48.6 months (8.6–59.1; IQR=12.2) for the 17 subjects without progressions.” (opens the source at this quote in a new tab)
“These data not only provide an alternative to standard chemotherapy for these subgroups of patients, but this success has led to an interest in exploring efficacy in patients as a first-line therapy. In fact, these data have directly led to the development of two Children’s Oncology Group phase III studies in newly diagnosed pLGG patients both with and without NF1 comparing standard chemotherapy to selumetinib.” (opens the source at this quote in a new tab)

“Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment.” (opens the source at this quote in a new tab)

“The median follow-up for patients on strata 1, 3, and 4 without events are 60.4, 60.4, and 58.1 months, and 5-year PFS/OS were 30.8%/88.9%, 54.2%/100%, and 51.0%/100%, respectively.” (opens the source at this quote in a new tab)

Selumetinib versus carboplatin and vincristine as first-line therapy: COG ACNS1831 and ACNS1833

“MEK inhibitors, including selumetinib, trametinib, mirdametinib, binimetinib, and cobimetinib, provide active inhibition of ERK signaling by targeting MEK, a kinase downstream from BRAF in the MAPK pathway. Several have been studied in pLGG, with demonstrated safety and efficacy data available in the recurrent pLGG and NF1-associated pLGG populations, and selumetinib is currently in clinical trials for newly diagnosed patients (NCT03871257, NCT04166409).” (opens the source at this quote in a new tab)

“Selumetinib achieved objective response rates of 36–40% in recurrent or progressive pLGG [4]. This supported the initiation of a phase 3 trials (NCT04166409, NCT03871257) comparing selumetinib with standard chemotherapy in upfront settings that unfortunately closed early because of poor accrual [39].” (opens the source at this quote in a new tab)

Field	Registry record
Brief title	“A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma”
Overall status	“Active, not recruiting”

Field	Registry record
Brief title	“A Study of the Drugs Selumetinib vs. Carboplatin and Vincristine in Patients With Low-Grade Glioma”
Overall status	“Recruiting”

Trametinib with or without dabrafenib in relapsed or refractory BRAF V600-mutant LGG

“In 49 patients with BRAF V600-mutant glioma (LGG, n = 47) across all four study parts, independently assessed objective response rates were 15% (95% CI, 1.9 to 45.4) for monotherapy (n = 13) and 25% (95% CI, 12.1 to 42.2) for combination (n = 36). Adverse event-related treatment discontinuations were more common with monotherapy (54% v 22%).” (opens the source at this quote in a new tab)

“While large, prospective trials are still ongoing (NCT03363217), retrospective analyses show promising objective response rates in recurrent pLGG, supporting drug class efficacy in this population (34–36). Interim results of a phase 2 study of single-agent trametinib demonstrated an overall response rate of around 47% (complete, partial, or minor response) in pLGG and a 60% response rate using volumetric assessments in patients with NF1-associated plexiform neurofibroma (33, 44).” (opens the source at this quote in a new tab)

Type II RAF inhibitor tovorafenib: current approval limited to relapsed or refractory disease

“On April 23, 2024, FDA granted accelerated approval to tovorafenib, a type II RAF kinase inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (pLGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.” (opens the source at this quote in a new tab)

“Tovorafenib is indicated as monotherapy for the treatment of patients 6 months of age and older with paediatric LGG harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation, who have progressed after one or more prior systemic therapies” (opens the source at this quote in a new tab)

Treatment exposure, discontinuation, and crossover in the first-line randomized comparison

“Twelve patients who were assigned to receive dabrafenib plus trametinib discontinued treatment, most commonly because of progressive disease (in 5 of 73 [7%]); in the chemotherapy group, 9 completed treatment and 16 discontinued, also most commonly because of progressive disease (in 9 of 37 [24%]). In the chemotherapy group, 9 patients had centrally confirmed progression and crossed over to receive dabrafenib plus trametinib.” (opens the source at this quote in a new tab)
“The median duration of exposure was 17.4 months with dabrafenib and 7.8 months with carboplatin; exposures to trametinib and vincristine were similar to those with dabrafenib and carboplatin, respectively” (opens the source at this quote in a new tab)

Dabrafenib plus trametinib in adults with recurrent BRAF V600E low-grade glioma in the ROAR basket trial

“In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1–47·8). Nine (69%; 95% CI 39–91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses.” (opens the source at this quote in a new tab)
“Median duration of response by independent radiology review was 27·5 months (95% CI 3·8–39·5; six events [all progressions]).” (opens the source at this quote in a new tab)
“Adverse events led to dose reductions in 22 (38%) patients, interruptions in 24 (41%) patients, and permanent discontinuation in five (9%) patients” (opens the source at this quote in a new tab)

Design, dosing, and statistical assumptions of the first-line randomized comparison

“Patients were randomly assigned in a 2:1 ratio to receive a combination of oral dabrafenib divided into two equal doses per day (<12 years of age, 5.25 mg per kilogram of body weight per day; ≥12 years of age, 4.5 mg per kilogram per day) plus trametinib once daily (<6 years of age, 0.032 mg per kilogram; ≥6 years, 0.025 mg per kilogram) or standard chemotherapy (carboplatin plus vincristine) according to the doses and schedule used in the Children’s Oncology Group A9952 trial.” (opens the source at this quote in a new tab)
“Liquid formulations of dabrafenib and trametinib were available.” (opens the source at this quote in a new tab)
“We estimated that the enrollment of 102 patients would provide at least 80% power to detect a relative increase of 30% in the overall response (which was estimated at 50% with dabrafenib plus trametinib and 20% with chemotherapy) in the primary analyses by independent assessment.” (opens the source at this quote in a new tab)

Sites, baseline histology, and participants randomized but not treated in the first-line comparison

“From September 2018 through December 2020, a total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive chemotherapy) at 58 sites in 20 countries” (opens the source at this quote in a new tab)
“The most frequent investigator-determined histologic types of glioma were pilocytic astrocytoma (in 34 patients), ganglioglioma (in 30), low-grade glioma not otherwise specified (in 20), and pleomorphic xanthoastrocytoma (in 11).” (opens the source at this quote in a new tab)
“Four patients in the chemotherapy group withdrew before receiving treatment on the basis of a decision by the parent or guardian (in 3 patients) or by the investigator (in 1 patient).” (opens the source at this quote in a new tab)

Deaths during the first-line randomized comparison

“No deaths were reported among the patients who received dabrafenib plus trametinib; 1 death was reported (from low-grade glioma) in the chemotherapy group. This death occurred more than 30 days after the last dose of randomized treatment.” (opens the source at this quote in a new tab)

Population, prior therapy, and dosing in the ROAR low-grade glioma cohort

“In the low-grade glioma cohort, 13 patients were included in the ITT population. Median age was 33 years (range 18–58) and median time since diagnosis was 6·9 years.” (opens the source at this quote in a new tab)
“All patients had previous surgery, eight (62%) had received previous radiotherapy, five (38%) had received previous chemotherapy, and two (15%) had received previous bevacizumab.” (opens the source at this quote in a new tab)
“Patients received oral dabrafenib (150 mg orally twice daily) and oral trametinib (2 mg orally once daily) until unacceptable toxicity, disease progression, or death.” (opens the source at this quote in a new tab)

Adverse events across the ROAR glioma cohorts

“The most common adverse events across both cohorts combined were fatigue (29 [50%] of 58), headache (25 [43%]), nausea (20 [34%]), and pyrexia (19 [33%]); 31 (53%) patients experienced grade 3 or 4 events, most commonly fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).” (opens the source at this quote in a new tab)

Design of the TRAM-01 phase 2 basket trial of single-agent trametinib

“The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups.” (opens the source at this quote in a new tab)
“Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers.” (opens the source at this quote in a new tab)

Published 2024 update: first-line targeted therapy approvals and tovorafenib's regulatory designations, with unresolved duration and late-effect questions

“Until recently, targeted therapy as first-line therapy for pLGG was only acceptable in the context of clinical trials.” (opens the source at this quote in a new tab)
“Taking into consideration recently published data regarding dabrafenib plus trametinib for patients with pLGG and BRAF V600 mutations, FDA and EMA have approved the use of this combination as first-line treatment for pediatric patients ≥1 year of age with low-grade glioma and a BRAF V600E mutation requiring systemic therapy” (opens the source at this quote in a new tab)
“Furthermore, tovorafenib-a type II RAF inhibitor- was recently granted rare pediatric disease designation for the treatment of pLGG harboring activating RAF alteration that disproportionately affects children and is now included in the LOGGIC Firefly 2 trial” (opens the source at this quote in a new tab)
“Tovorafenib was also granted FDA approval for LGG with RAF alteration relapsing after first-line therapy” (opens the source at this quote in a new tab)
“It should be highlighted that the main unknown issues of targeted treatments remain optimal duration as well as potentially unknown very late effects, thus, additional studies are required.” (opens the source at this quote in a new tab)