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LGG-46. TRAMETINIB THERAPY IN PEDIATRIC PATIENTS WITH LOW-GRADE GLIOMAS (LGG) WITH BRAF GENE FUSION; A DISEASE-SPECIFIC COHORT IN THE FIRST PEDIATRIC TESTING OF TRAMETINIB

ABSTRACT: Abstract BACKGROUND LGG is the most prevalent childhood brain tumor. BRAF fusions drive constitutive activation of BRAF and tumorigenesis. We report results of trametinib, a MEK1/2 inhibitor, in pediatric patients with LGG with BRAF fusion. METHODS This phase 1/2 trial (NCT02124772) enrolled pediatric patients (?18 y) with refractory/recurrent tumors. We report results from interim analysis of pediatric patients with LGG harboring BRAF fusion. Trametinib was dosed at 4 dose levels in part A (0.0125, 0.025, 0.04, and 0.032 mg/kg/d) and at 0.025 mg/kg/day in the expansion cohort. Tumor assessments were performed every 8 weeks by MRI, including T2-FLAIR sequences, using RANO criteria. RESULTS Twenty-three patients were enrolled across cohorts. Median age of patients was 8 y (range, 2-18) and 13 of 23 were male. At data cutoff, 15 patients were ongoing. One patient discontinued with progressive disease (PD) at 35 weeks, 4 due to adverse events (AEs), 2 per investigator discretion, and 1 per consent withdrawal. The most common treatment-related AEs were diarrhea (14), rash (13), paronychia (9), and maculopapular rash (8). There were no deaths on study. Confirmed partial responses were observed in 3 patients by investigator and 1 patient by independent review. No patients had best response of PD. All responses were ongoing at the data cutoff (all >1 y), and 12 patients had ongoing stable disease (49-121 weeks). CONCLUSION In pediatric patients with pretreated LGG and BRAF fusion, trametinib was well tolerated, with 1 independently confirmed RANO response, and most patients were without PD >1 y.

SUBMITTER: Bouffet E

PROVIDER: S-EPMC6012791 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND There is a lack of treatment options for HGG and LGG patients. BRAFV600E mutations are uncommon in glioma, with a poor long-term prognosis. Combined BRAF/MEK inhibition extends progression-free survival (PFS) and overall survival (OS) in BRAF V600E–mutated melanoma, non small-cell lung cancer, and anaplastic thyroid cancer. METHODS This phase 2, open-label trial (NCT02034110) evaluated dabrafenib (BRAF inhibitor, 150mg BID) plus trametinib (MEK inhibitor, 2mg QD) in patients with BRAF V600E mutations in 9 rare tumor types, including HGG and LGG. Eligible patients had histologically-confirmed recurrent or progressive glioma (LGG:WHO grade 1 or 2; HGG:WHO grade 3 or 4), with HGG patients required to have received radiotherapy and first-line chemotherapy, or concurrent chemoradiation. Treatment continued until unacceptable toxicity, disease progression, or death. Primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. RESULTS Interim analysis (IA) #14 (data cutoff: April 2, 2018) reported additional 3 months follow-up, with 49 patients enrolled (HGG, n=39; LGG, n=10) and 3 patients not evaluable for response. In HGG patients, ORR was 27% (10/37; 95%CI: 13.8%-44.1%), including CR (n=1), PR (n=9), and SD (n=11), with 16 patients currently ongoing treatment. In LGG patients, ORR was 56% (5/9; 95%CI: 26.8%-79.3%), including PR (n=5) and SD (n=4), with 6 patients currently ongoing treatment. OS, PFS, and DOR will be presented (IA#15). In HGG patients, adverse events (AEs) included fatigue (33%), headache (31%), rash (28%), and pyrexia (23%); grade 3/4 AEs included neutropenia (8%) and fatigue (5%). In LGG patients, AEs included headache (70%), fatigue, pyrexia (60% each), nausea, and arthralgia (50% each); grade 3/4 AEs included fatigue (20%). CONCLUSIONS Dabrafenib plus trametinib demonstrated promising efficacy in patients with recurrent or refractory BRAF V600E?mutated HGG or LGG, with manageable AEs and no new safety signals.

Dataset Information

LGG-46. TRAMETINIB THERAPY IN PEDIATRIC PATIENTS WITH LOW-GRADE GLIOMAS (LGG) WITH BRAF GENE FUSION; A DISEASE-SPECIFIC COHORT IN THE FIRST PEDIATRIC TESTING OF TRAMETINIB

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