BRAF and MEK inhibitors

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36]

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36]

Results on the use of the BRAF V600E inhibitor dabrafenib demonstrated a 44% overall response rate (1 complete response and 13 partial responses) by central review in children with BRAF V600 variants and relapsed or refractory low-grade gliomas. The median duration of response was 26 months. The disease control rate (complete response plus partial response plus stable disease) was 78%. The therapy was well tolerated, although 91% of patients experienced side effects such as fatigue (34%), rash (31%), and pyrexia (28%). Nine of 32 patients had grade 3 to grade 4 toxicities, 10 patients required dose modifications, and 2 patients discontinued treatment, including 1 child who had disseminated intravascular coagulation with hypertension. In this pediatric study, no cases of squamous cell carcinoma of the skin or keratoacanthoma were encountered.[37]

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36]

A phase I/II study of trametinib as a single agent for patients with BRAF V600E variants and low-grade gliomas enrolled 13 pediatric patients. The objective response rate for these 13 patients was assessed by independent review using Response Assessment in Neuro-Oncology (RANO) 2017 response criteria for low-grade gliomas that employ T2-fluid attenuated inversion recovery (FLAIR) rather than contrast enhancement.[38]

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36] › A phase I/II study of trametinib as a single agent for patients with BRAF V600E variants and low-grade gliomas enrolled 13 pediatric patients. The objective response rate for these 13 patients was assessed by independent review using Response Assessment in Neuro-Oncology (RANO) 2017 response criteria for low-grade gliomas that employ T2-fluid attenuated inversion recovery (FLAIR) rather than contrast enhancement.[38]

Two of 13 patients (15%) achieved partial responses, and 6 patients (46%) had stable disease.

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36] › A phase I/II study of trametinib as a single agent for patients with BRAF V600E variants and low-grade gliomas enrolled 13 pediatric patients. The objective response rate for these 13 patients was assessed by independent review using Response Assessment in Neuro-Oncology (RANO) 2017 response criteria for low-grade gliomas that employ T2-fluid attenuated inversion recovery (FLAIR) rather than contrast enhancement.[38]

The 24-month PFS rate was 50%.

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36]

A phase I/II study that evaluated the combination of dabrafenib and trametinib enrolled 34 patients with BRAF V600E variants and low-grade gliomas and 2 patients with BRAF V600E variants and high-grade gliomas. The objective response rate for these 36 patients was assessed by independent review using RANO 2017 response criteria for low-grade glioma that employ T2-FLAIR rather than contrast enhancement.[38]

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36] › A phase I/II study that evaluated the combination of dabrafenib and trametinib enrolled 34 patients with BRAF V600E variants and low-grade gliomas and 2 patients with BRAF V600E variants and high-grade gliomas. The objective response rate for these 36 patients was assessed by independent review using RANO 2017 response criteria for low-grade glioma that employ T2-FLAIR rather than contrast enhancement.[38]

Nine of 36 patients (25%) achieved partial responses, and 23 patients (64%) had stable disease.

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36] › A phase I/II study that evaluated the combination of dabrafenib and trametinib enrolled 34 patients with BRAF V600E variants and low-grade gliomas and 2 patients with BRAF V600E variants and high-grade gliomas. The objective response rate for these 36 patients was assessed by independent review using RANO 2017 response criteria for low-grade glioma that employ T2-FLAIR rather than contrast enhancement.[38]

The 24-month PFS rate was 80%.

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36] › A phase I/II study that evaluated the combination of dabrafenib and trametinib enrolled 34 patients with BRAF V600E variants and low-grade gliomas and 2 patients with BRAF V600E variants and high-grade gliomas. The objective response rate for these 36 patients was assessed by independent review using RANO 2017 response criteria for low-grade glioma that employ T2-FLAIR rather than contrast enhancement.[38]

The most common treatment-related adverse events in the dabrafenib-plus-trametinib group were pyrexia (50%) and dry skin (42%). Adverse events leading to discontinuation of therapy occurred in 22% of patients, a lower rate than observed for patients who received single-agent trametinib (54%).

For patients whose tumors have BRAF V600E variants, the focus of clinical research efforts is on the evaluation of BRAF inhibitors in combination with MEK inhibitors. Such combinations are approved for the treatment of adult cancers with BRAF V600E variants and are more effective than either BRAF inhibitors or MEK inhibitors used as single agents.[36] › A phase I/II study that evaluated the combination of dabrafenib and trametinib enrolled 34 patients with BRAF V600E variants and low-grade gliomas and 2 patients with BRAF V600E variants and high-grade gliomas. The objective response rate for these 36 patients was assessed by independent review using RANO 2017 response criteria for low-grade glioma that employ T2-FLAIR rather than contrast enhancement.[38]

The FDA approved the trametinib-plus-dabrafenib combination for adult and pediatric patients aged 1 year and older with unresectable or metastatic solid tumors with BRAF V600E variants who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication includes pediatric patients aged 1 year and older with BRAF V600E variants and low-grade gliomas.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia.

The phase I component of the PBTC-029 trial showed the following results:[39]

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › The phase I component of the PBTC-029 trial showed the following results:[39]

Selumetinib was tolerated at a daily dose of 25 mg/m2.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › The phase I component of the PBTC-029 trial showed the following results:[39]

The most common adverse events leading to patient discontinuation of treatment were rash, paronychia, and asymptomatic creatine phosphokinase (CPK) elevation.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia.

Stratum 1 of the phase II component of this trial was for patients with BRAF genomic alterations.[40]

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › Stratum 1 of the phase II component of this trial was for patients with BRAF genomic alterations.[40]

Nine of 25 patients (36%) achieved a partial response, with responses occurring for both BRAF V600E patients and for patients with BRAF gene fusions.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › Stratum 1 of the phase II component of this trial was for patients with BRAF genomic alterations.[40]

The 2-year PFS rate was 70% for stratum 1 patients.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia.

Stratum 3 of the phase II component of this trial was for patients with NF1-associated low-grade gliomas.[40]

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › Stratum 3 of the phase II component of this trial was for patients with NF1-associated low-grade gliomas.[40]

The 2-year event-free survival rate for this group was 96%.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › Stratum 3 of the phase II component of this trial was for patients with NF1-associated low-grade gliomas.[40]

10 of 25 patients (40%) achieved partial responses.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia.

Stratum 4 of the phase II component of this trial was for patients with recurrent optic pathway and hypothalamic low-grade gliomas.[41]

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › Stratum 4 of the phase II component of this trial was for patients with recurrent optic pathway and hypothalamic low-grade gliomas.[41]

Six of 25 patients (24%) had a partial response, and an additional 14 of 25 patients (56%) had stable disease.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › Stratum 4 of the phase II component of this trial was for patients with recurrent optic pathway and hypothalamic low-grade gliomas.[41]

The 2-year PFS rate was 78%.

The MEK inhibitor selumetinib has been studied in a phase I/II clinical trial for children with low-grade gliomas (PBTC-029 [NCT01089101]). The most common toxicities across all strata were grade 1 and grade 2 CPK elevation, diarrhea, hypoalbuminemia, elevated aspartate aminotransferase (AST), and rash. Rare grade 3 and grade 4 toxicities included elevated CPK, rash, neutropenia, emesis, and paronychia. › Stratum 4 of the phase II component of this trial was for patients with recurrent optic pathway and hypothalamic low-grade gliomas.[41]

Of the 19 patients evaluable for visual acuity, 4 had improvements in visual acuity, with an additional 13 having stable findings.

In 2024, the FDA granted accelerated approval to tovorafenib (a type 2 RAF inhibitor) for the treatment of patients aged 6 months or older with relapsed or refractory low-grade glioma harboring a BRAF fusion or rearrangement or BRAF V600 variant. Approval was based on the results of a study of 137 patients (77 patients in the primary cohort [arm 1] and 60 patients in an extension cohort [arm 2]) who were treated with tovorafenib. The study was designed using Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, which defines response as the reduction in the T1-Gd positive measurements.[42]

In 2024, the FDA granted accelerated approval to tovorafenib (a type 2 RAF inhibitor) for the treatment of patients aged 6 months or older with relapsed or refractory low-grade glioma harboring a BRAF fusion or rearrangement or BRAF V600 variant. Approval was based on the results of a study of 137 patients (77 patients in the primary cohort [arm 1] and 60 patients in an extension cohort [arm 2]) who were treated with tovorafenib. The study was designed using Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, which defines response as the reduction in the T1-Gd positive measurements.[42]

Using the RANO-HGG criteria, the overall response rate (ORR) was 67% for patients in arm 1, with a median duration of response (DOR) of 16.6 months.

In 2024, the FDA granted accelerated approval to tovorafenib (a type 2 RAF inhibitor) for the treatment of patients aged 6 months or older with relapsed or refractory low-grade glioma harboring a BRAF fusion or rearrangement or BRAF V600 variant. Approval was based on the results of a study of 137 patients (77 patients in the primary cohort [arm 1] and 60 patients in an extension cohort [arm 2]) who were treated with tovorafenib. The study was designed using Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, which defines response as the reduction in the T1-Gd positive measurements.[42]

When the data was analyzed using Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, which defines response as the reduction in the T2/FLAIR signal, the ORR was 51%, with a median DOR of 13.8 months.