LGG-44. A PHASE I DOSE ESCALATION TRIAL OF THE MEK1/2 INHIBITOR MEK162 (BINIMETINIB) IN CHILDREN WITH LOW-GRADE GLIOMAS AND OTHER RAS/RAF PATHWAY-ACTIVATED TUMORS

Ras/Raf/MEK/ERK pathway activation is the primary driver of most pediatric low-grade gliomas (LGG). MEK162 is an orally bioavailable MEK1/2 inhibitor.

The primary objective of this first-in-children multi-institutional open-label dose-escalation trial was to determine the maximum tolerated dose (MTD) of MEK162 oral suspension in children.

Children aged 1-18 years with recurrent, refractory or progressive LGG and other non-hematologic malignancies associated with Ras/Raf pathway activation were enrolled according to a 3 + 3 dose-escalation design. Partial response (PR) and radiographic progressive disease (PD) were defined as ≥50% decrease and ≥25% increase in 2-dimensional tumor measurements.

Nineteen eligible patients, aged 2-15 (median 9) years, including 17 with LGG, were enrolled and began treatment at five dose levels, from 16 to 32mg/m2/dose twice daily. There were no dose limiting toxicities (DLTs) in 18 DLT-evaluable patients; MTD was not reached. Most common drug-attributable grade ≥2 toxicities included (all grade 2 unless specified): asymptomatic elevated creatine kinase in 9 patients (53%; 1 grade 4, 3 grade 3), acneiform or maculopapular rash in 8 (47%; 2 grade 3), dry skin in 5 (29%; 2 grade 3), and lymphopenia in 4 (24%; 1 grade 3). To date, 4 patients have had clinical or radiographic PD (3 with LGG), and 4 LGG patients have had sustained PR. Twelve LGG patients have completed at least 36 weeks therapy, with a median 29% decrease in 2-dimensional tumor measurements.

MEK162 is well tolerated in this pediatric population, with evidence of antitumor activity. A phase II study is ongoing.